Cyclopropyl derivatives and methods of use

ABSTRACT

The disclosure relates to cyclopropyl derivatives and methods of use. In some embodiments, the disclosure relates to methods of managing medical disorders with pharmaceutical compositions disclosed herein administered to subject in need thereof. In certain embodiments, the disclosure relates to methods of managing mental disorders, mood disorders, pain, and fibromyalgia and related conditions with pharmaceutical compositions disclosed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/477,848 filed Apr. 21, 2011, hereby incorporated by reference in itsentirety.

ACKNOWLEDGEMENTS

This invention was made with government support under Grants R01DA023224 and R01 DA022599 awarded by the National Institutes of Health.The government has certain rights in the invention.

FIELD

The disclosure relates to cyclopropyl derivatives and methods of use. Insome embodiments, the disclosure relates to methods of managing medicaldisorders with pharmaceutical compositions disclosed herein administeredto subject in need thereof. In certain embodiments, the disclosurerelates to methods of managing mental disorders, mood disorders, pain,fibromyalgia, and related conditions with pharmaceutical compositionsdisclosed herein.

BACKGROUND

Fibromyalgia is a medical disorder characterized by chronic widespreadpain and allodynia. Fibromyalgia is frequently comorbid with psychiatricconditions such as depression, anxiety, and stress-related disorders.Currently, there is no cure for fibromyalgia. Medical therapies withanti-depressants have demonstrated the ability to reduce symptoms.Milnacipran is a cyclopropylamide and a selective norepinephrine andserotonin reuptake inhibitor (SNRI) approved by the FDA for themanagement of fibromyalgia. A significant percentage of patientsdiscontinue taking milnacipran due to adverse events such as nausea,palpitations, depression, increased heart rate, constipation, andheadaches. Other adverse events reported when taking milnaciparaninclude increases in heart rate and blood pressure, serotonin syndrome,seizures, hepatotoxicity, hyponatremia, abnormal bleeding, activation ofmania and dysuria. Thus, there is a need to identify improved therapies.

Bonnarud et al., J Med Chem, 1987, 30, 318-325 disclose cyclopropanecarbocylic acid derivatives. See also U.S. Pat. No. 4,567,288 and U.S.Published Application No. 2008/0051604. The authors report uses asantidepressants and for the treatment of pain. Certain cyclopropylderivatives are also disclosed in Davies & Denton, Chem. Soc. Rev.,2009, 38, 3061-3071; Pelphrey et al., Chem. Sci., 2010, 1, 254-257,Davies et al., Tetrahedron Letters, (1996) 37(24), 4133-4136, Denton &Davies, Organic Letters, (2009) 11(4), 787-790. See also U.S. Pat. No.7,385,064.

SUMMARY

This disclosure relates to cyclopropyl derivatives and methods of use.In some embodiments, the disclosure relates to methods of managing,treating, or preventing medical disorders with pharmaceuticalcompositions disclosed herein administered in an effective amount tosubject in need thereof. In certain embodiments, the disclosure relatesto methods of managing mental disorders, mood disorders, pain, andfibromyalgia and related conditions with pharmaceutical compositionsdisclosed herein. In certain embodiments, the disclosure relates tocompounds comprising the following formula I:

and salts, prodrugs, or esters thereof wherein,

A ring is a carbocyclyl, aryl, or heterocyclyl;

n is 0, 1, 2, 3, 4, or 5;

X and Y are each the same or different O, S, NR⁴;

R¹ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R¹ is optionally substituted with one or more, thesame or different, R⁵;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁵;

R³ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³ is optionally substituted with one ormore, the same or different, R⁵;

R⁴ is hydrogen, alkyl, hydroxy, amino, formyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁴ is optionally substituted with one or more, thesame or different, R⁵;

R⁵ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁵ is optionally substituted with one or more, thesame or different, R⁶; and

R⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the disclosure relates to a compositioncomprising a compound disclosed herein in greater than 60%, 70%, 80%,90%, 95%, 98%, 99%, or 99.5% diastereomeric excess.

In certain embodiments, the disclosure relates to an isolatedcomposition of a compound disclosed herein in substantially pure form.

In certain embodiments, the disclosure relates to a pharmaceuticalcomposition comprising a compound disclosed herein or pharmaceuticallyacceptable salt or prodrug thereof.

In certain embodiments, the disclosure relates to a pharmaceuticalcomposition disclosed herein further comprising a second therapeuticagent.

In certain embodiments, the disclosure relates to a method of treatingor preventing a mental or neurological disorder comprising administeringan effective amount of a pharmaceutical composition disclosed herein toa subject diagnosed with, exhibiting symptoms of, or at risk for amental or neurological disorder.

In certain embodiments, the disclosure relates to methods of preparingcompounds disclosed herein comprising mixing the starting material andreagents under conditions such that the products are formed.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a scheme illustrating the synthesis of racemic cyclopropaneamines.

FIG. 2 shows a scheme illustration synthesis of certain diastereomers ofcyclopropane amines.

FIG. 3 shows data on the anti-allodynic effects of SNRI analogs andclonidine. All compounds were administered i.t. and paw withdrawalthreshold was determined before (baseline) and following drug treatment(treatment) in a similar manner. Maximally effective doses were givenfor clonidine (10 μg), Milnacipran (30 μg), HD-286 (3 μg) and HD-288 (3μg). N=8-10/group. *, significantly different from clonidine, p≦0.05.

FIG. 4 shows data on the effects of clonidine, milnacipran and HD-288 onrotarod performance in SNL rats. Rats were trained to walk on a rotarodapparatus during 5 minute trials on two successive days. The rotarod wasaccelerated from 2 to 5 rpm over a 5 min period and the time until therat fell from the rotarod was recorded. Each trial was a maximum of 5min in duration. Shown are the mean±SEM for time spent on the rotarodbefore (baseline) or after (Treatment) drug administration (N=10-13 pergroup). * significantly different from Baseline, p≦0.05.

FIG. 5 shows illustrative schemes for preparing compounds disclosedherein.

DETAILED DISCUSSION

The disclosure relates to cyclopropyl derivatives and methods of use. Insome embodiments, the disclosure relates to methods of managing medicaldisorders with pharmaceutical compositions disclosed herein administeredto subject in need thereof. In certain embodiments, the disclosurerelates to methods of managing mental disorders, mood disorders, pain,and fibromyalgia and related conditions with pharmaceutical compositionsdisclosed herein.

Compounds

In certain embodiments, the disclosure relates to compounds comprisingthe following formula I:

and salts, prodrugs, or esters thereof wherein,

A ring is a carbocyclyl, aryl, or heterocyclyl;

n is 0, 1, 2, 3, 4, or 5;

X and Y are each the same or different O, S, NR⁴;

R¹ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R¹ is optionally substituted with one or more, thesame or different, R⁵;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁵;

R³ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³ is optionally substituted with one ormore, the same or different, R⁵;

R⁴ is hydrogen, alkyl, hydroxy, amino, formyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁴ is optionally substituted with one or more, thesame or different, R⁵;

R⁵ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁵ is optionally substituted with one or more, thesame or different, R⁶; and

R⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the A ring is aryl or heteroaryl;

n is 0, 1, 2, or 3;

X is oxygen;

Y is NR⁴;

R¹ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R¹ is optionally substituted with one or more, thesame or different, R⁵;

R² is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R² is optionally substituted with one ormore, the same or different, R⁵;

R³ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³ is optionally substituted with one ormore, the same or different, R⁵;

R⁴ is hydrogen, alkyl, hydroxy, amino, formyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁴ is optionally substituted with one or more, thesame or different, R⁵;

R⁵ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁵ is optionally substituted with one or more, thesame or different, R⁶; and

R⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the A ring is aryl or heteroaryl;

n is 0, 1, 2, or 3;

X is oxygen;

Y is NR⁴ wherein R² and R⁴ and the atoms to which they are attached forma heterocyclyl optionally substituted with one or more, the same ordifferent R⁵;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁵;

R² is hydrogen or alkyl;

R³ is hydrogen or alkyl;

R⁴ is hydrogen or alkyl;

R⁵ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl,carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, orheterocyclyl, wherein R⁵ is optionally substituted with one or more, thesame or different, R⁶; and

R⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, the A ring is aryl;

n is 0, 1, 2, or 3;

X is oxygen;

Y is NH;

R¹ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R¹ is optionally substituted with one ormore, the same or different, R⁵;

R² is hydrogen or alkyl;

R³ is hydrogen or alkyl;

R⁵ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl,methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, orN-methyl-N-ethylsulfamoyl.

In certain embodiments, the disclosure relates to a compound of formulaI, wherein formula I is formula IA, IB, IC, or ID wherein:

formula IA is

formula IB is

formula IC is

andformula ID is

In certain embodiments, the A ring is aryl or heteroaryl.

In certain embodiments, the A ring is aryl or heteroaryl and X is oxygenor NR⁴.

In certain embodiments, the A ring is aryl or heteroaryl, R³ is hydrogenor C₁₋₄alkyl and X is oxygen or NR⁴.

In certain embodiments, the A ring is aryl or heteroaryl, R² is hydrogenor C₁₋₄alkyl, Y is NR⁴ or oxygen, and X is oxygen or NR⁴.

In certain embodiments, the A ring is aryl or heteroaryl, R¹ is ahydrogen, halogen, or alkoxy, X is oxygen, Y is NR⁴, and R² is hydrogenor C₁₋₄alkyl.

In certain embodiments, the A ring is aryl or heteroaryl, Y is NR⁴ oroxygen, and X is oxygen or NR⁴.

In certain embodiments, the A ring is phenyl, napthyl or biphenyl.

In certain embodiments, the A ring is phenyl, napthyl or biphenyl and Xis oxygen or NR⁴.

In certain embodiments, the A ring is phenyl, napthyl or biphenyl, R³ ishydrogen or C₁₋₄alkyl and X is oxygen or NR⁴.

In certain embodiments, the A ring is phenyl, napthyl or biphenyl, Y isNR⁴ or oxygen and X is oxygen or NR⁴.

In certain embodiments, the A ring is phenyl, napthyl or biphenyl, R² ishydrogen or C₁₋₄alkyl, Y is NR⁴, and X is oxygen.

In certain embodiments, the A ring is phenyl, napthyl or biphenyl, R¹ isa hydrogen, halogen, or alkoxy, X is oxygen, and R² is hydrogen orC₁₋₄alkyl.

In certain embodiments, X is oxygen.

In certain embodiments, X is NR⁴, wherein R⁴ is hydrogen or C₁₋₄alkyl.

In certain embodiments, Y is NR⁴, wherein R⁴ is hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ is hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ is methyl or ethyl.

In certain embodiments, R² is hydrogen or C₁₋₄alkyl.

In certain embodiments, R² is methyl or ethyl.

In certain embodiments, R¹ is a hydrogen, halogen, or C₁₋₄alkoxy.

In certain embodiments, R¹ is methoxy or ethoxy.

In certain embodiments, n is 0, 1, 2, or 3;

In certain embodiments, n is 0, 1 or 2.

In certain embodiments, n is 1 or 2.

In certain embodiments, the disclosure relates to a compound of formulaIA, wherein the A ring is aryl. In certain embodiments, the A ring isphenyl. In certain embodiments, the A ring is napthyl. In certainembodiments, the A ring is biphenyl. In certain embodiments, the A ringis aryl and X is oxygen or NR⁴. In certain embodiments, the A ring isaryl, R³ is hydrogen or C₁₋₄alkyl and X is oxygen. In certainembodiments, the A ring is aryl, Y is NR⁴ or oxygen, X is oxygen. Incertain embodiments, the A ring is aryl, R₂ is hydrogen or C₁₋₄alkyl, Yis NR⁴, and X is oxygen. In certain embodiments, the A ring is aryl, R¹is a hydrogen, halogen, or alkoxy, X is oxygen, and R² is hydrogen orC₁₋₄alkyl. In certain embodiment, R⁴ is C₁₋₄alkyl.

In certain embodiments, the disclosure relates to a compound of formulaIB, wherein the A ring is aryl. In certain embodiments, the A ring isphenyl. In certain embodiments, the A ring is napthyl. In certainembodiments, the A ring is biphenyl. In certain embodiments, the A ringis aryl and X is oxygen or NR⁴. In certain embodiments, the A ring isaryl, R³ is hydrogen or C₁₋₄alkyl and X is oxygen. In certainembodiments, the A ring is aryl, Y is NR⁴ or oxygen, and X is oxygen. Incertain embodiments, the A ring is aryl, R² is hydrogen or C₁₋₄alkyl, Yis NR⁴, and X is oxygen. In certain embodiments, the A ring is aryl, R¹is a hydrogen, halogen, or alkoxy, X is oxygen, and R² is hydrogen orC₁₋₄alkyl. In certain embodiment, R⁴ is C₁₋₄alkyl.

In certain embodiments, the disclosure relates to compositionscomprising a compound of formula IA, in greater than 60%, 70%, 80%, 90%,95%, or 98% diastereomeric excess wherein the A ring is aryl, X isoxygen, Y is NR⁴, R³ is C₁₋₄alkyl, R² is hydrogen or C₁₋₄alkyl, R¹ is ahydrogen, halogen, or alkoxy, and n is 1 or 2. In certain embodiments,the A ring is phenyl. In certain embodiments, A ring is phenylsubstituted with one or more halogens. In certain embodimentssubstituted at the 3 and 4 position of the phenyl ring. In certainembodiments, the A ring is napthyl. In certain embodiments, the A ringis biphenyl. In certain embodiments, R² is C₁₋₄alkyl. In certainembodiment, R⁴ is C₁₋₄alkyl.

In certain embodiments, the disclosure relates to a compositioncomprising a compound of formula IB, in greater than 60%, 70%, 80%, 90%,95%, or 98% diastereomeric excess wherein the A ring is aryl, X isoxygen, Y is NR⁴, R³ is C₁₋₄alkyl, R² is hydrogen or C₁₋₄alkyl, R¹ is ahydrogen, halogen, or alkoxy, and n is 1 or 2. In certain embodiment, R⁴is C₁₋₄alkyl.

In some embodiments, the disclosure relates to a compound selected from:

-   (1S,2S)-methyl    2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate,-   (1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic acid,-   (1S,2S)-methyl    1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1S,2S)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,-   (1S,2S)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylic    acid,-   (1S,2S)-methyl    1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,    and-   (1S,2S)-1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid, or salts thereof.

In certain embodiment the disclosure relates to a compound selectedfrom:

-   (1R,2R)-methyl    2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate,-   (1R,2R)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic acid,-   (1R,2R)-methyl    1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,-   (1R,2R)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,-   (1R,2R)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylic    acid,-   (1R,2R)-methyl    1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,    and-   (1R,2R)-1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylic    acid, or salts thereof.

In certain embodiments, the disclosure relates to compounds disclosedherein substituted with one or more substituents.

Compound Preparation

Methods for the preparation of certain cyclopropyl derivatives aredisclosed in Pelphrey et al., Chem. Sci., 2010, 1, 254-257, Davies etal., Tetrahedron Letters, (1996) 37(24), 4133-4136, Denton & Davies,Organic Letters, (2009) 11(4), 787-790, Davies & Denton, Chem. Soc.Rev., 2009, 38, 3061-3071. See also U.S. Pat. No. 4,567,288, U.S. Pat.No. 7,385,064, and U.S. Published Application No. 2008/0051604 allhereby incorporated by reference.

In certain embodiments, the disclosure relates to a process of producinga compound of formula I comprising mixing a metal catalyst, a compoundof formula II, formula II

and a compound of formula III, formula III

under conditions such that a compound of formula I is formed. In certainembodiments a compound of formula IA, IB, IC, or IC is formed. Incertain embodiments, the metal catalyst is a chiral catalyst such asRh₂(S-biTISP)₂, Rh₂(S-DOSP)₄, or Rh₂(S-PTAD)₄.

Therapeutic Applications

In some embodiments, the disclosure relates to methods of treating orpreventing mental disorders with pharmaceutical compositions disclosedherein administered to subject in need thereof. Examples of mentaldisorders include, but are not limited to, anxiety or mood disorders,depression, major depression disorder; schizophrenia, paranoid,undifferentiates, residual, catatonic or disorganized, subchronic orchronic with acute exacerbation, in remission; delusional (paranoid)disorder; brief reactive psychosis; schizophreniform disorder;schizoaffective disorder; induced psychotic disorder; atypicalpsychosis; personality disorders, paranoid, schizoid, schizotypal,antisocial; and bipolar disorders, maniac, hypomaniac, dysthymic orcyclothymic disorders; substance-induced major depression; andsubstance-induced psychotic disorder. Also included are adjustmentdisorders, eating disorders, sleep disorders, sexual identity disorders,and impulse control disorders.

In anxiety disorders, anxiety interferes with normal functioning.Representative classifications include specific phobias, generalizedanxiety disorder, social anxiety disorder, panic disorder, agoraphobia,obsessive-compulsive disorder and post-traumatic stress disorder.

Subjects with mood disorders typically report intense and sustainedsadness, melancholia or despair. Diagnosis can range from depression,major depression or clinical depression (milder but still prolongeddepression can be diagnosed as dysthymia). Bipolar disorder (also knownas manic depression) involves abnormally “high” or pressured moodstates, known as mania or hypomania, alternating with normal ordepressed mood.

Representative psychotic disorders include schizophrenia, and delusionaldisorder. Subjects with these disorders typically exhibit patterns ofdisbelief and often language use and perception can become disordered(e.g. delusions, thought disorder, hallucinations). Schizoaffectivedisorder is a category used for individuals showing aspects of bothschizophrenia and affective disorders. Schizotypy is a category used forindividuals showing some of the characteristics associated withschizophrenia but without meeting cut-off criteria.

Personality may be considered disordered if judged to be abnormallyrigid and maladaptive. Representative personality disorders includethose sometimes classed as eccentric (e.g. paranoid, schizoid andschizotypal personality disorders), to those sometimes classed asdramatic or emotional (antisocial, borderline, histrionic ornarcissistic personality disorders) or those seen as fear-related(avoidant, dependent, or obsessive-compulsive personality disorders).

Eating disorders involve disproportionate concern in matters of food andweight. Categories of disorder in this area include anorexia nervosa,bulimia nervosa, exercise bulimia or binge eating disorder.

Sleep disorders such as insomnia involve disruption to normal sleeppatterns, or a feeling of tiredness despite sleep appearing normal.

Sexual and gender identity disorders may be diagnosed, includingdyspareunia, gender identity disorder and ego-dystonic homosexuality.Various kinds of paraphilia are considered mental disorders (sexualarousal to objects, situations, or individuals that are consideredabnormal or harmful to the person or others).

Subjects with impulse control disorder are abnormally unable to resistcertain urges or impulses. Representative examples include tic disorderssuch as Tourette's syndrome, and disorders such as kleptomania orpyromania, and gambling addiction.

Subjects with dissociative identity disorder suffer disturbances oftheir self-identity, memory and general awareness of themselves andtheir surroundings. Representative examples include depersonalizationdisorder or dissociative identity disorder itself (which has also beencalled multiple personality disorder, or “split personality), memory orcognitive disorders include amnesia or various kinds of old agedementia.

Representative childhood disorders autism spectrum disorders,oppositional defiant disorder and conduct disorder, and attentiondeficit hyperactivity disorder (ADHD).

In some embodiments, the disclosure relates to the management ofneuropathic pain comprising administering a pharmaceutical compositiondisclosed herein to a subject at risk of, exhibiting symptoms ordiagnosed with neuropathic pain. Neuropathic pain refers to painassociated with abnormal sensations sometimes called dysesthesias, whichoccur spontaneously and allodynias. Neuropathic pain may have continuousand/or episodic (paroxysmal) components. Common qualities of neuropathicpain include burning or coldness, “pins and needles” sensations,numbness and itching. Neuropathic pain may result from disorders of theperipheral nervous system or the central nervous system (brain andspinal cord). Thus, neuropathic pain may be divided into peripheralneuropathic pain, central neuropathic pain, or mixed (peripheral andcentral) neuropathic pain. Central neuropathic pain is typically foundin subjects with spinal cord injury, multiple sclerosis, and strokes.Common causes of painful peripheral neuropathies are herpes zosterinfection, HIV-related neuropathies, nutritional deficiencies, toxinexposures, remote manifestations of malignancies, genetic, and immunemediated disorders or physical trauma to a nerve trunk. Neuropathic painis common in cancer as a direct result of cancer on peripheral nerves(e.g., compression by a tumor), or as a side effect of chemotherapy,radiation injury or surgery.

In some embodiments, the disclosure relates to the management offibromyalgia comprising administering a pharmaceutical compositiondisclosed herein to a subject at risk of, exhibiting symptoms ordiagnosed with fibromyalgia. Fibromyalgia is a medical disordercharacterized by chronic widespread pain and a heightened and painfulresponse to pressure.

In some embodiments, the disclosure relates to the management of painfrom menstrual cramps comprising administering a pharmaceuticalcomposition disclosed herein to a woman.

Pharmaceutical Formulations

Pharmaceutical compositions disclosed herein may be in the form ofpharmaceutically acceptable salts, as generally described below. Somepreferred, but non-limiting examples of suitable pharmaceuticallyacceptable organic and/or inorganic acids are hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citricacid, as well as other pharmaceutically acceptable acids known per se(for which reference is made to the references referred to below).

When the compounds of the disclosure contain an acidic group as well asa basic group, the compounds of the disclosure may also form internalsalts, and such compounds are within the scope of the disclosure. Whenthe compounds contain a hydrogen-donating heteroatom (e.g. NH), thisdisclosure contemplates salts and/or isomers formed by transfer of saidhydrogen atom to a basic group or atom within the molecule, such as inthe case of an amino acid.

Pharmaceutically acceptable salts of the compounds include the acidaddition and base salts thereof. Suitable acid addition salts are formedfrom acids which form non-toxic salts. Examples include the acetate,adipate, aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts. Suitable base salts are formedfrom bases which form non-toxic salts. Examples include the aluminium,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine and zinc salts. Hemisalts of acids and bases may also beformed, for example, hemisulphate and hemicalcium salts. For a review onsuitable salts, see Handbook of Pharmaceutical Salts: Properties,Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporatedherein by reference.

The compounds described herein may be administered in the form ofprodrugs. A prodrug can include a covalently bonded carrier whichreleases the active parent drug when administered to a mammaliansubject. Prodrugs can be prepared by modifying functional groups presentin the compounds in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent compounds.Prodrugs include, for example, compounds wherein a hydroxyl group isbonded to any group that, when administered to a mammalian subject,cleaves to form a free hydroxyl group. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholfunctional groups in the compounds. Methods of structuring a compound asprodrugs can be found in the book of Testa and Mayer, Hydrolysis in Drugand Prodrug Metabolism, Wiley (2006). Typical prodrugs form the activemetabolite by transformation of the prodrug by hydrolytic enzymes, thehydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxidesor the cleavage of esters of inorganic acids.

Pharmaceutical compositions for use in the present disclosure typicallycomprise an effective amount of a compound and a suitable pharmaceuticalacceptable carrier. The preparations may be prepared in a manner knownper se, which usually involves mixing the at least one compoundaccording to the disclosure with the one or more pharmaceuticallyacceptable carriers, and, if desired, in combination with otherpharmaceutical active compounds, when necessary under asepticconditions. Reference is again made to U.S. Pat. No. 6,372,778, U.S.Pat. No. 6,369,086, U.S. Pat. No. 6,369,087, and U.S. Pat. No. 6,372,733and the further references mentioned above, as well as to the standardhandbooks, such as the latest edition of Remington's PharmaceuticalSciences.

Generally, for pharmaceutical use, the compounds may be formulated as apharmaceutical preparation comprising at least one compound and at leastone pharmaceutically acceptable carrier, diluent or excipient and/oradjuvant, and optionally one or more further pharmaceutically activecompounds.

The pharmaceutical preparations of the disclosure are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 1 and 1000 mg, and usually between 5 and 500 mg, ofthe at least one compound of the disclosure, e.g. about 10, 25, 50, 100,200, 300 or 400 mg per unit dosage.

The compounds can be administered by a variety of routes including theoral, ocular, rectal, transdermal, subcutaneous, intravenous,intramuscular, spinal, epidural, or intranasal routes, depending mainlyon the specific preparation used. The compound will generally beadministered in an “effective amount”, by which is meant any amount of acompound that, upon suitable administration, is sufficient to achievethe desired therapeutic or prophylactic effect in the subject to whichit is administered. Usually, depending on the condition to be preventedor treated and the route of administration, such an effective amountwill usually be between 0.01 to 1000 mg per kilogram body weight of thepatient per day, more often between 0.1 and 500 mg, such as between 1and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg,per kilogram body weight of the patient per day, which may beadministered as a single daily dose, divided over one or more dailydoses. The amount(s) to be administered, the route of administration andthe further treatment regimen may be determined by the treatingclinician, depending on factors such as the age, gender and generalcondition of the patient and the nature and severity of thedisease/symptoms to be treated. Reference is again made to U.S. Pat. No.6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087, and U.S.Pat. No. 6,372,733 and the further references mentioned above, as wellas to the standard handbooks, such as the latest edition of Remington'sPharmaceutical Sciences.

For an oral administration form, the compound can be mixed with suitableadditives, such as excipients, stabilizers or inert diluents, andbrought by means of the customary methods into the suitableadministration forms, such as tablets, coated tablets, hard capsules,aqueous, alcoholic, or oily solutions. Examples of suitable inertcarriers are gum arabic, magnesia, magnesium carbonate, potassiumphosphate, lactose, glucose, or starch, in particular, corn starch. Inthis case, the preparation can be carried out both as dry and as moistgranules. Suitable oily excipients or solvents are vegetable or animaloils, such as sunflower oil or cod liver oil. Suitable solvents foraqueous or alcoholic solutions are water, ethanol, sugar solutions, ormixtures thereof. Polyethylene glycols and polypropylene glycols arealso useful as further auxiliaries for other administration forms. Asimmediate release tablets, these compositions may containmicrocrystalline cellulose, dicalcium phosphate, starch, magnesiumstearate and lactose and/or other excipients, binders, extenders,disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, the compositions maybe prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. Suitablepharmaceutical formulations for administration in the form of aerosolsor sprays are, for example, solutions, suspensions or emulsions of thecompounds of the disclosure or their physiologically tolerable salts ina pharmaceutically acceptable solvent, such as ethanol or water, or amixture of such solvents. If required, the formulation can alsoadditionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous, spinal, epidural, or intravenous administration, thecompounds, if desired with the substances customary therefore such assolubilizers, emulsifiers or further auxiliaries are brought intosolution, suspension, or emulsion. The compounds of formula I can alsobe lyophilized and the lyophilizates obtained used, for example, for theproduction of injection or infusion preparations. Suitable solvents are,for example, water, physiological saline solution or alcohols, e.g.ethanol, propanol, glycerol, sugar solutions such as glucose or mannitolsolutions, or mixtures of the various solvents mentioned. The injectablesolutions or suspensions may be formulated according to known art, usingsuitable non-toxic, parenterally-acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodiumchloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, theformulations may be prepared by mixing the compounds of formula I with asuitable non-irritating excipient, such as cocoa butter, syntheticglyceride esters or polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

In certain embodiments, it is contemplated that these compositions canbe extended release formulations. Typical extended release formationsutilize an enteric coating. A barrier is applied to oral medication thatcontrols the location in the digestive system where it is absorbed.Enteric coatings prevent release of medication before it reaches thesmall intestine. Enteric coatings may contain polymers ofpolysaccharides, such as maltodextrin, xanthan, scleroglucan dextran,starch, alginates, pullulan, hyaloronic acid, chitin, chitosan and thelike; other natural polymers, such as proteins (albumin, gelatin etc.),poly-L-lysine; sodium poly(acrylic acid);poly(hydroxyalkylmethacrylates) (for examplepoly(hydroxyethylmethacrylate)); carboxypolymethylene (for exampleCarbopol™); carbomer; polyvinylpyrrolidone; gums, such as guar gum, gumarabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellangum, gum tragacanth, agar, pectin, gluten and the like; poly(vinylalcohol); ethylene vinyl alcohol; polyethylene glycol (PEG); andcellulose ethers, such as hydroxymethylcellulose (HMC),hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC),ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose(CMHEC), hydroxypropylmethyl-cellulose (HPMC),hydroxypropylethylcellulose (HPEC) and sodium carboxymethylcellulose (NaCMC); as well as copolymers and/or (simple) mixtures of any of the abovepolymers. Certain of the above-mentioned polymers may further becrosslinked by way of standard techniques.

The choice of polymer will be determined by the nature of the activeingredient/drug that is employed in the composition of the disclosure aswell as the desired rate of release. In particular, it will beappreciated by the skilled person, for example in the case of HPMC, thata higher molecular weight will, in general, provide a slower rate ofrelease of drug from the composition. Furthermore, in the case of HPMC,different degrees of substitution of methoxyl groups and hydroxypropoxylgroups will give rise to changes in the rate of release of drug from thecomposition. In this respect, and as stated above, it may be desirableto provide compositions of the disclosure in the form of coatings inwhich the polymer carrier is provided by way of a blend of two or morepolymers of, for example, different molecular weights in order toproduce a particular required or desired release profile.

Combination Therapies

With regard to mental disorders, compounds disclosed herein may beadminister in combinations with other psychiatric medications, such asantidepressants, anxiolytics, anticonvulsants, antipsychotics andstimulants such as anti-inflammatory agents.

Representative antidepressants include monoamine oxidase inhibitors(MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants(TeCAs), selective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs) and others.

Representative selective and non-selective MAOIs include benmoxin,hydralazine, iproclozide, iproniazid, isocarboxazid, isoniazid,mebanazine, nialamide, octamoxin, phenelzine, pheniprazine,phenoxypropazine, pivalylbenzhydrazine, procarbazine, safrazine,caroxazone, echinopsidine, furazolidone, linezolid, tranylcypromine,brofaromine, metralindole, minaprine, moclobemide, pirlindole,toloxatone, lazabemide, pargyline, rasagiline, selegiline, resveratrol,curcumin, catechin, desmethoxyyangonin, epicatechin, hydroxytyrosol, andpiperine.

Representative TCAs include amitriptyline, amitriptylinoxide,butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin,dimetacrine dosulepin/dothiepin, doxepin, imipramine, imipraminoxide,lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline,noxiptiline, pipofezine, propizepine, protriptyline, quinupramine,amineptine, iprindole, opipramol, tianeptine, trimipramine.Representative TeCAs include, amoxapine, maprotiline, mazindol,mianserin, mirtazapine, setiptiline, ciclazindol, esmirtazapine, andoxaprotiline.

Representative SSRIs include citalopram, dapoxetine, escitalopram,fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, andzimelidine.

Representative SNRIs include venlafaxine, desvenlafaxine, duloxetine,milnacipran, levomilnacipran, sibutramine, and bicifadine.

Other representative anti-depressants include mianserin, mirtazapine,atomoxetine, mazindol, reboxetine, viloxazine, bupropion, tianeptine,and agomelatine.

Representative anxiolytics include alprazolam, chlordiazepoxide,clonazepam, diazepam, lorazepam, buspirone, tandospirone, gepirone,hydroxyzine, and pregabalin.

Representative anticonvulsants include lithium, valproic acid,lamotrigine, carbamazepine, oxcarbazepine, and gabapentin.

Representative antipsychotics include haloperidol, droperidol,chlorpromazine, fluphenazine, perphenazine, prochlorperazine,thioridazine, trifluoperazine, mesoridazine, periciazine, promazine,triflupromazine, levomepromazine, promethazine, pimozide,chlorprothixene, clopenthixol, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, amisulpride, asenapine, paliperidone, iloperidone,zotepine, sertindole, aripiprazole, bifeprunox, and cannabidiol.

Representative stimulants include caffeine nicotine, amphetamine,methamphetamine, methylenedioxymethamphetamine, troparil, lometopane,methylphenidate, bupropion atomoxetine, reboxetine, modafinil, ampalex,carphedon, and yohimbine.

Suitable anti-inflammatory compounds include both steroidal andnon-steroidal structures. Suitable non-limiting examples of steroidalanti-inflammatory compounds are corticosteroids such as hydrocortisone,cortisol, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethasone dipropionates, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylesters, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone, fludrocortisone, difluorosone diacetate, fluocinolone,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortamate, meprednisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone.Mixtures of the above steroidal anti-inflammatory compounds may also beused.

Non-limiting examples of non-steroidal anti-inflammatory compoundsinclude nabumetone, celecoxib, etodolac, nimesulide, apasone, gold,oxicams, such as piroxicam, isoxicam, meloxicam, tenoxicam, sudoxicam,the salicylates, such as aspirin, disalcid, benorylate, trilisate,safapryn, solprin, diflunisal, and fendosal; the acetic acidderivatives, such as diclofenac, fenclofenac, indomethacin, sulindac,tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin,fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; thefenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, andtolfenamic acids; the propionic acid derivatives, such as ibuprofen,naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and the pyrazoles,such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, andtrimethazone.

In other embodiments, the compounds are administered in combination withmedications that prevent indigestion or gastritis such as H2 receptorantagonists (cimetidine, ranitidine, famotidine, and nizatidine) orproton pump inhibitors such as omeprazole, lansoprazole,dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole.

These compounds could be co-administered with analgesics to treat acuteor chronic pain conditions. Examples of such analgesics would be opioidagonists (including morphine, codeine, methadone, meperidine, etc.),α₂-adrenergic agonists (such as clonidine), gabapentin, andcholinesterase inhibitors (such as donepezil).

Terms

When describing the compounds for use in the disclosure, the terms usedare to be construed in accordance with the following definitions, unlessa context dictates otherwise.

A “chiral metal catalyst” refers to a catalytic metal complex where theligands have one or more chiral centers. Examples include chiral2-(2-aryl- or 2-alkyl-sulfonylamino)phenyl-4-phenyl-1,3-oxazolines asligands for copper-catalyzed enantioselective cyclopropanation reactionof olefins described in Ichiyanagi et al, Tetrahedron, 1997, 53(28),9599-9610 and Rh₂(S-biTISP)₂, Rh₂(S-DOSP)₄, or Rh₂(S-PTAD)₄ catalysts asdisclosed in Denton & Davis, Organic Letters, 2009, 11(4), 787-790,Davis et al., Tetrahedron Letters, 1996, 37(24) 4133-4136, and U.S. Pat.No. 7,385,064 hereby incorporated by reference. Chiral copper, rhodium,and ruthenium catalysts are representative of those contemplated by thisdisclosure. Typically, the chiral centers in the ligands inducecatalytic conversion in enantiomeric or diastereomeric excess if presentin the reaction product. Replacing the chiral ligands with theirenantiomers will typically invert the stereochemistry of the reactionproduct.

As used herein, “alkyl” means a noncyclic straight chain or branched,unsaturated or saturated hydrocarbon such as those containing from 1 to10 carbon atoms, while the term “lower alkyl” or “C₁₋₄alkyl” has thesame meaning as alkyl but contains from 1 to 4 carbon atoms. The term“higher alkyl” has the same meaning as alkyl but contains from 7 to 20carbon atoms. Representative saturated straight chain alkyls includemethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl,n-nonyl, and the like; while saturated branched alkyls includeisopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.Unsaturated alkyls contain at least one double or triple bond betweenadjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”,respectively). Representative straight chain and branched alkenylsinclude ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like; while representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

Non-aromatic mono or polycyclic alkyls are referred to herein as“carbocycles” or “carbocyclyl” groups. Representative saturatedcarbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like; while unsaturated carbocycles include cyclopentenyl andcyclohexenyl, and the like.

“Heterocarbocycles” or heterocarbocyclyl” groups are carbocycles whichcontain from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur which may be saturated or unsaturated (but notaromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen heteroatom maybe optionally quaternized. Heterocarbocycles include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“Aryl” means an aromatic carbocyclic monocyclic or polycyclic ring suchas phenyl or naphthyl. Polycyclic ring systems may, but are not requiredto, contain one or more non-aromatic rings, as long as one of the ringsis aromatic.

As used herein, “heteroaryl” refers an aromatic heterocarbocycle having1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom, including both mono- and polycyclicring systems. Polycyclic ring systems may, but are not required to,contain one or more non-aromatic rings, as long as one of the rings isaromatic. Representative heteroaryls are furyl, benzofuranyl,thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl,pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl,pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that theuse of the term “heteroaryl” includes N-alkylated derivatives such as a1-methylimidazol-5-yl substituent.

As used herein, “heterocycle” or “heterocyclyl” refers to mono- andpolycyclic ring systems having 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom. Themono- and polycyclic ring systems may be aromatic, non-aromatic ormixtures of aromatic and non-aromatic rings. Heterocycle includesheterocarbocycles, heteroaryls, and the like.

“Alkylthio” refers to an alkyl group as defined above with the indicatednumber of carbon atoms attached through a sulfur bridge. An example ofan alkylthio is methylthio, (i.e., —S—CH3).

“Alkoxy” refers to an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, s-butoxy, t-butoxy.

“Alkylamino” refers an alkyl group as defined above with the indicatednumber of carbon atoms attached through an amino bridge. An example ofan alkylamino is methylamino, (i.e., —NH—CH3).

“Alkanoyl” refers to an alkyl as defined above with the indicated numberof carbon atoms attached through a carbonyl bride (i.e., —(C═O)alkyl).

“Alkylsulfonyl” refers to an alkyl as defined above with the indicatednumber of carbon atoms attached through a sulfonyl bridge (i.e.,—S(═O)₂alkyl) such as mesyl and the like, and “Arylsulfonyl” refers toan aryl attached through a sulfonyl bridge (i.e., —S(═O)₂aryl).

“Alkylsulfamoyl” refers to an alkyl as defined above with the indicatednumber of carbon atoms attached through a sulfamoyl bridge (i.e.,—NHS(═O)2alkyl), and an “Arylsulfamoyl” refers to an alkyl attachedthrough a sulfamoyl bridge (i.e., (i.e., —NHS(═O)2aryl).

“Alkylsulfinyl” refers to an alkyl as defined above with the indicatednumber of carbon atoms attached through a sulfinyl bridge (i.e.—S(═O)alkyl).

The term “substituted” refers to a molecule wherein at least onehydrogen atom is replaced with a substituent. When substituted, one ormore of the groups are “substituents.” The molecule may be multiplysubstituted. In the case of an oxo substituent (“═O”), two hydrogenatoms are replaced. Example substituents within this context may includehalogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl,carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, —NRaRb, —NR aC(═O)Rb,—NRaC(═O)NRaNRb, —NRaC(═O)ORb, —NRaSO2Rb, —C(═O)Ra, —C(═O)ORa,—C(═O)NRaRb, —OC(═O)NRaRb, —ORa, —SRa, —SORa, —S(═O)2Ra, —OS(═O)2Ra and—S(═O)2ORa. Ra and Rb in this context may be the same or different andindependently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino,alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl,heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl.

The term “optionally substituted,” as used herein, means thatsubstitution is optional and therefore it is possible for the designatedatom to be unsubstituted.

As used herein, “salts” refer to derivatives of the disclosed compoundswhere the parent compound is modified making acid or base salts thereof.Examples of salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines, alkylamines, ordialkylamines; alkali or organic salts of acidic residues such ascarboxylic acids; and the like. In preferred embodiment the salts areconventional nontoxic pharmaceutically acceptable salts including thequaternary ammonium salts of the parent compound formed, and non-toxicinorganic or organic acids. Preferred salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

“Subject” refers any animal, preferably a human patient, livestock, ordomestic pet.

The term “prodrug” refers to an agent that is converted into abiologically active form in vivo. Prodrugs are often useful because, insome situations, they may be easier to administer than the parentcompound. They may, for instance, be bioavailable by oral administrationwhereas the parent compound is not. The prodrug may also have improvedsolubility in pharmaceutical compositions over the parent drug. Aprodrug may be converted into the parent drug by various mechanisms,including enzymatic processes and metabolic hydrolysis.

As used herein, the terms “prevent” and “preventing” include theprevention of the recurrence, spread or onset. It is not intended thatthe present disclosure be limited to complete prevention. In someembodiments, the onset is delayed, or the severity of the disease isreduced.

As used herein, the terms “treat” and “treating” are not limited to thecase where the subject (e.g. patient) is cured and the disease iseradicated. Rather, embodiments, of the present disclosure alsocontemplate treatment that merely reduces symptoms, and/or delaysdisease progression.

A “mental disorder” or “mental illness” or “mental disease” or“psychiatric or neuropsychiatric disease or illness or disorder” refersto mood disorders (e.g., depression, mania, and bipolar disorders),psychotic disorders (e.g., schizophrenia, schizoaffective disorder,schizophreniform disorder, delusional disorder, brief psychoticdisorder, and shared psychotic disorder), personality disorders, anxietydisorders (e.g., obsessive-compulsive disorder) as well as other mentaldisorders such as substance-related disorders, childhood disorders,dementia, autistic disorder, adjustment disorder, delirium,multi-infarct dementia, and Tourette's disorder as described inDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition,(DSM IV).

EXPERIMENTAL General Information

¹H Nuclear Magnetic Resonance (NMR) spectra were typically recorded on aVarian spectrometer at either 300, 400, 500, or 600 MHz, and ¹³C NMR ateither 75, 100, or 125 MHz with the sample solvent being CDCl₃. Thefollowing abbreviations are used to explain multiplicities: s, singlet;d, doublet; t, triplet; q, quartet; dd, doublet of doublet; m,multiplet. Coupling constants were taken directly from the spectra andare uncorrected. IR spectra were obtained using a Thermo ScientificNicolet iS10 FT-IR and reported in units of cm⁻¹. Melting points weremeasured on an electrothermal melting point apparatus and areuncorrected. High Resolution Mass spectral (HRMS) determinations(pos-APCI) were performed by the Instrument Center of the Department ofChemistry, Emory University. Elemental analysis was performed atAtlantic Microlabs Inc., Norcross Ga. Optical rotations were measured atthe sodium D line (589 nm) and reported as follows: [α]_(D) ²⁵concentration (c in g/100 mL) and solvent. All rotations are measured at25.0° C. Enantiomeric excess was determined by Varian Pro Star highperformance liquid chromatography (HPLC) using chiral analytical columns(Chiralcel OD, Chiralcel OD-H, Chiralcel OJ, Chiralpak AD-H, ChiralpakAS-H, Chiralpack AD-RH, (R,R)-Whelk, or (S,S-Whelk)(UV detection at 254or 273 nm). Chiral columns and conditions are specified for individualcompounds. Analytical TLC was performed on 0.25 mm E. Merck silica gel(60F-254) plates using UV light. Phosphomolybdic acid (PMA), KMnO₄,Ninhydrin or dinitrophenylhydrazine (DNP) was used as visualizing agentif necessary.

Glassware was dried in an oven overnight prior to use. Reactions weretypically conducted under an atmosphere of argon. Flash columnchromatography was performed on Merck silica gel 60 (230-400 mesh).Hexanes, toluene, THF, DCM, Diethyl ether and acetonitrile were dried bypassage through activated alumina columns in a solvent purificationsystem prior to use. All other reagents were purchased from Aldrich,Alfa Aesar, or Acros chemical companies and used without additionalpurification unless noted. Rhodium catalysts like Rh₂(OAc)₄,Rh₂(S-DOSP)₄, Rh₂(R-DOSP)₄, Rh₂(S-PTAD)₄, were obtained from lab sourcesand were used as is.

(E)-buta-1,3-dienylbenzene (1)

Methyltriphenylphosphine bromide (178 g, 50 mmol) was added to a flamedried 1 L flask and THF (500 mL) was added. The reaction flask wascooled to 0° C. and Potassium ter-butoxide (84 g, 75 mmol) and stirredfor 5 hours at 0° C. (E)-3-phenylacrylaldehyde (66 g, 50 mmol) in THF(100 mL) was added drop wise over 1 h, then stirred for 16 additionalhours. The reaction was poured into H₂O (1 L) and extracted into pentane(3×200 mL). The combined organic layers were washed with brine, driedover MgSO₄. Hexane was added to the reaction flask. Triphenyl phosphineoxide precipitates out. The reaction mixture was filtered throughcelite/silica gel and the solvent was removed under reduced pressure.The crude material was purified using Kughlerrohr distillation (85° C.)to obtain product as a colorless oil in 87% yield (56 g). ¹H NMR (500MHz, CDCl₃): δ7.32 (m, 5H), 6.78 (dd, J=10.4 Hz, 1H), 6.54 (m, 2H), 5.34(d, J=16.8 Hz, 1H), 5.17 (d, J=10.4 Hz, 1H).

Synthesis of Aryl Diazoacetates (2) Methyl 2-diazo-2-phenyl acetate (2a)

This was prepared according to a modified procedure provided in Baum etal., Synth. Commun. 1987, 17, 1709-16 hereby incorporated by reference.Methyl phenylacetate (4.5 g, 30 mmol) and p-acetamidobenzene sulfonylazide (p-ABSA) (7.93 g, 33 mmol) were dissolved in acetonitrile (100 mL)and cooled to 0° C. in an ice bath. 1,8-Diazabicycloundec-7-ene (DBU)(5.48 mL, 36 mmol) was added in one portion and the reaction was stirredat 0° C. for 1 hour, then 3 additional hours at room temperature. Thereaction was poured into saturated NH₄Cl solution (100 mL) and extractedinto diethyl ether (2×100 mL). The combined ether layers were dried overMgSO₄, filtered and concentrated to obtain the crude product. The crudematerial was purified by column chromatography (SiO₂, 95:5 petroleumether/diethyl ether) to obtain 4.59 g (80% yield) of colored oil. ¹H NMR(500 MHz, CDCl₃): δ3.84 (s, 3H), 7.46 (m, 5H).

Methyl 2-(4-bromophenyl)-2-diazoacetate (2b)

In a flame dried round bottom flask, 2-(4-bromophenyl)acetic acid (50mmol, 1 eq.) was dissolved in MeOH (50 mL) and cooled to 0° C. Acetylchloride (60 mmol, 1.2 eq.) was added drop wise at 0° C. The resultantreaction mixture was stirred at rt for overnight. The reaction mixturewas poured in to a separation funnel having ethyl ether and saturatedNH₄Cl solution. Extracted twice; combined organic layers were washedwith brine, dried over MgSO₄ and concentrated in vacuo. The crude methylacetate mixture was taken to next step without further purification.

The resultant methyl acetate was dissolved in acetonitrile andp-acetamidobenzene sulfonyl azide (p-ABSA) (60 mmol, 1.2 eq.) was added.The reaction mixture was cooled to 0° C. and 1,8-Diazabicycloundec-7-ene(DBU) (120 mmol, 2 eq.) was added drop wise at 0° C. The reactionmixture was stirred at rt for overnight. Reaction mixture was quenchedwith saturated aqueous NH₄Cl solution, extracted twice with diethylether (2×100 mL); combined organic layers were washed with brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel using 9:1 hexane/Et₂O as eluant toisolate 11.16 g (93% yield) of yellow crystalline solid. ¹H NMR (400MHz, CDCl₃) δ 3.87 (s, 3H) 7.36 (d, J=8.61 Hz, 2H) 7.50 (d, J=8.61 Hz,2H).

Methyl 2-([1,1′-biphenyl]-4-yl)-2-diazoacetate (2c)

In a flame dried round bottom flask, 2-([1,1′-biphenyl]-4-yl)acetic acid(50 mmol, 1 eq.) was dissolved in MeOH (50 mL) and cooled to 0° C.Acetyl chloride (60 mmol, 1.2 eq.) was added drop wise at 0° C. Theresultant reaction mixture was stirred at rt for overnight. The reactionmixture was poured in to a separation funnel having ethyl ether andsaturated NH₄Cl solution. Extracted twice; combined organic layers werewashed with brine, dried over MgSO₄ and concentrated in vacuo. The crudemethyl acetate mixture was taken to next step without furtherpurification.

The resultant methyl acetate was dissolved in acetonitrile andp-acetamidobenzene sulfonyl azide (p-ABSA) (60 mmol, 1.2 eq.) was added.The reaction mixture was cooled to 0° C. and 1,8-Diazabicycloundec-7-ene(DBU) (120 mmol, 2 eq.) was added drop wise at 0° C. The reactionmixture was stirred at rt for overnight. Reaction mixture was quenchedwith saturated aqueous NH₄Cl solution, extracted twice with diethylether (2×100 mL); combined organic layers were washed with brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel using 9:1 hexane/Et₂O as eluant toisolate 9.6 g (80% yield) of yellow crystalline solid. ¹H NMR (400 MHz,CDCl₃) δ 3.90 (s, 3H) 7.33-7.39 (m, 1H) 7.45 (t, J=7.63 Hz, 2H)7.54-7.66 (m, 6H).

Methyl 2-diazo-2-(naphthalene-2-yl)acetate (2d)

2-(Naphthalen-2-yl)acetic acid (5.00 g, 24.8 mmol) was dissolved inmethanol (90 mL). Acetyl chloride (3.68 g, 46.8 mmol) was then added andthe reaction was stirred overnight. The reaction was concentrated toobtain the crude acetate in 97% yield (5.25 g). This compounds was usedwithout further purification. ¹H NMR (500 MHz, CDCl₃) δ 3.70 (s, 3H),3.75 (m, 2H), 7.40 (d, J=8.5 Hz, 1H), 7.44 (m, 2H), 7.72 (s, 1H), 7.80(m, 3H).

Methyl 2-(naphthalen-2-yl)acetate (5.00 g, 24.9 mmol) and p-ABSA (7.49g, 31.2 mmol) were dissolved in acetonitrile (35 mL) and cooled to 0° C.DBU (7.51 mL, 49.9 mmol) was added in one portion and the reaction wasstirred at 0° C. for 1 hour, then 3 additional hours at roomtemperature. The reaction was poured into saturated NH₄Cl solution andextracted into diethyl ether. The combined ether layers were dried overMgSO₄, filtered and concentrated to obtain the crude product. The crudematerial was purified by column chromatography (SiO₂, 95:5 petroleumether/diethyl ether) to obtain 4.59 g (80% yield) of yellow crystallinesolid. ¹H NMR (400 MHz, CDCl₃) δ 3.92 (s, 3H) 7.42-7.51 (m, 2H) 7.54(dd, J=8.80, 1.76 Hz, 1H) 7.81 (d, J=8.22 Hz, 2H) 7.86 (d, J=8.61 Hz,1H) 8.02 (s, 1H).

Methyl 2-diazo-2-(3,4-dichlorophenyl)acetate (2e)

3,4-Dichlorophenylacetic acid (5.50 g, 26.8 mmol) was dissolved in MeOH(100 mL). Acetyl chloride (4.21 g, 53.7 mmol) was then added and thereaction was stirred overnight. The reaction was concentrated to obtainthe crude acetate in 93% yield (5.47 g). This compound was used withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ 3.61 (m, 2H), 3.79 (s,3H), 7.14 (d, 2H, J=8.5 Hz), 7.42 (d, 2H, J=8.5 Hz).

Methyl 2-(3,4-dichlorophenyl)acetate (5.33 g, 24.3 mmol) and p-ABSA(7.03 g, 30.4 mmol) were dissolved in acetonitrile (35 mL) and cooled to0° C. DBU (7.40 mL, 48.7 mmol) was added in one portion and the reactionwas stirred at 0° C. for 1 hour, then 3 additional hours at roomtemperature. The reaction was poured into saturated NH₄Cl solution andextracted into diethyl ether. The combined ether layers were dried overMgSO₄, filtered and concentrated to obtain the crude product. The crudematerial was purified by column chromatography (SiO₂, 95:5 petroleumether/diethyl ether) to obtain 4.96 g (83% yield) of yellow crystallinesolid. ¹H NMR (400 MHz, CDCl₃) δ 3.88 (s, 3H) 7.29 (dd, J=8.61, 2.35 Hz,1H) 7.43 (d, J=8.61 Hz, 1H) 7.64 (d, J=1.96 Hz, 1H).

Methyl 2-(2-chlorophenyl)-2-diazoacetate (2f)

In a flame dried round bottom flask, 2-(2-chlorophenyl)acetic acid (55mmol, 1 eq.) was dissolved in MeOH (100 mL) and cooled to 0° C. Acetylchloride (66 mmol, 1.2 eq.) was added drop wise at 0° C. The resultantreaction mixture was stirred at rt for overnight. The reaction mixturewas poured in to a separation funnel having ethyl ether and saturatedNH₄Cl solution. Extracted twice; combined organic layers were washedwith brine, dried over MgSO₄ and concentrated in vacuo. The crude methylacetate mixture was taken to next step without further purification.

The resultant methyl acetate was dissolved in acetonitrile andp-acetamidobenzene sulfonyl azide (p-ABSA) (66 mmol, 1.2 eq.) was added.The reaction mixture was cooled to 0° C. and 1,8-Diazabicycloundec-7-ene(DBU) (110 mmol, 2 eq.) was added drop wise at 0° C. The reactionmixture was stirred at rt for overnight. Reaction mixture was quenchedwith saturated aqueous NH₄Cl solution, extracted twice with diethylether (2×100 mL); combined organic layers were washed with brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel using 9:1 hexane/Et₂O as eluant toisolate 10.16 g (87% yield) of yellow crystalline solid. ¹H NMR (400MHz, CDCl₃) δ 3.85 (s, 3H) 7.23-7.36 (m, 2H) 7.43 (d, J=7.43 Hz, 1H)7.54 (d, J=7.04 Hz, 1H).

Methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate (2 g)

In a flame dried round bottom flask, 2-(3,4-dimethoxyphenyl)acetic acid(50 mmol, 1 eq.) was dissolved in MeOH (100 mL) and cooled to 0° C.Acetyl chloride (60 mmol, 1.2 eq.) was added drop wise at 0° C. Theresultant reaction mixture was stirred at rt for overnight. The reactionmixture was poured in to a separation funnel having ethyl ether andsaturated NH₄Cl solution. Extracted twice; combined organic layers werewashed with brine, dried over MgSO₄ and concentrated in vacuo. The crudemethyl acetate mixture was taken to next step without furtherpurification.

The resultant methyl acetate was dissolved in acetonitrile andp-acetamidobenzene sulfonyl azide (p-ABSA) (60 mmol, 1.2 eq.) was added.The reaction mixture was cooled to 0° C. and 1,8-Diazabicycloundec-7-ene(DBU) (120 mmol, 2 eq.) was added drop wise at 0° C. The reactionmixture was stirred at rt for overnight. Reaction mixture was quenchedwith saturated aqueous NH₄Cl solution, extracted twice with diethylether (2×100 mL); combined organic layers were washed with brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel using 9:1 hexane/Et₂O as eluant toisolate 11.12 g (94% yield) of yellow crystalline solid. ¹H NMR (400MHz, CDCl₃) δ 3.86 (s, 3H) 3.88 (s, 3H) 3.90 (s, 3H) 6.87-6.90 (m, 1H)7.19 (d, J=1.17 Hz, 1H) 7.26 (s, 1H).

Synthesis of Styrylcyclopropanecarboxylates (3) (E)-methyl1-phenyl-2-styrylcyclopropanecarboxylate (3a)

A solution of methyl 2-diazo-2-phenylacetate (176 mg, 1 mmol, and 1 eq.)in toluene (10 mL) was added by syringe pump over 1 h to a solution of(E)-buta-1,3-dienylbenzene (390.2 mg, 3 mmol, 3 eq.) and Rh₂(OAc)₄ (0.01mmol, 0.1 eq.) in toluene (10 mL) at rt. The reaction mixture wasstirred at rt for an additional 2 h, and then concentrated in vacuo.Crude reaction mixture was purified by flash chromatography on silicagel using 9:1 hexane/EtOAc as eluant to isolate 163 mg (93% yield) ofoily liquid. ¹H NMR (500 MHz, CDCl₃): δ 1.42 (m, 1H), 2.02 (m, 1H), 2.66(m, 1H), 3.52 (s, 3H), 5.18 (dd, J=15.5 Hz, 10.0 Hz, 1H), 6.52 (d,J=15.5 Hz, 1H), 7.05 (m, 3H), 7.12 (m, 2H), 7.25 (m, 5H), ¹³C NMR (300MHz, CDCl₃): δ 22.26 (CH₂), 31.65 (CH), 35.47 (C), 52.12 (CH₃), 125.6(CH), 126.8 (CH), 127.0 (CH), 127.8 (CH), 128.1 (CH), 128.5 (CH), 131.0(CH), 131.4 (CH), 135.6 (C), 136.8 (C), 173.7 (C), FTIR (neat): 1717,1271, 1244, 1193, 1159, 960, 752, 694 cm⁻¹. HRMS (EI) m/z calcd for[C₁₉H₁₈O₂Na₁]⁺ 301.1199. Found: 301.1194.

(E)-methyl 1-(4-bromophenyl)-2-styrylcyclopropanecarboxylate (3b)

A solution of methyl 2-(4-bromophenyl)-2-diazoacetate (510 mg, 2 mmol,and 1 eq.) in toluene (10 mL) was added by syringe pump over 1 h to asolution of (E)-buta-1,3-dienylbenzene (781 mg, 6 mmol, 3 eq.) andRh₂(OAc)₄ (8 mg, 0.02 mmol, 0.1 eq.) in toluene (10 mL) at rt. Thereaction mixture was stirred at rt for an additional 2 h, and thenconcentrated in vacuo. Crude reaction mixture was purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate671 mg (94% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.40 (dd,J=6.41, 4.88 Hz, 1H) 2.04 (dd, J=8.85, 4.58 Hz, 1H) 2.62-2.73 (m, 1H)3.59 (s, 3H) 5.17 (dd, J=15.87, 9.76 Hz, 1H) 6.55 (d, J=15.87 Hz, 1H)7.03-7.27 (m, 7H) 7.41 (d, J=8.24 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃): δ22.42, 31.83, 34.95, 52.42, 121.36, 125.75, 127.13, 127.98, 128.36,131.11, 131.67, 133.20, 134.81, 136.72, 173.35; FTIR (Neat): 1716, 1488,1270, 1242, 728 cm⁻¹; HRMS (pos-APCI) calcd for C₁₉H₁₈O₂ ⁷⁹Br:357.04847. Found 357.04834; HRMS (neg-APCI) calcd for C₁₉H₁₆O₂ ⁷⁹Br:355.03391. Found 355.03397.

(E)-methyl 1-([1,1′-biphenyl]-4-yl)-2-styrylcyclopropanecarboxylate (3c)

A solution of methyl 2-([1,1′-biphenyl]-4-yl)-2-diazoacetate (252 mg, 1mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump over 1 hto a solution of (E)-buta-1,3-dienylbenzene (390.2 mg, 3 mmol, 3 eq.)and Rh₂(OAc)₄ (4 mg, 0.01 mmol, 0.1 eq.) in toluene (10 mL) at rt. Thereaction mixture was stirred at rt for an additional 2 h, and thenconcentrated in vacuo. Crude reaction mixture was purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate297 mg (84% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.51 (dd,J=6.25, 4.73 Hz, 1H) 2.09 (dd, J=8.85, 4.58 Hz, 1H) 2.66-2.76 (m, 1H)3.67 (s, 3H) 5.26 (dd, J=15.87, 9.76 Hz, 1H) 6.60 (d, J=15.87 Hz, 1H)7.14 (t, J=7.78 Hz, 3H) 7.20 (d, J=7.02 Hz, 2H) 7.36 (d, J=7.93 Hz, 3H)7.44 (t, J=7.63 Hz, 2H) 7.56 (d, J=8.24 Hz, 2H) 7.62 (d, J=7.02 Hz, 2H);¹³C NMR (75 MHz, CDCl₃): δ 22.6, 32.1, 35.4, 52.6, 125.9, 126.7, 127.0,127.1, 127.2, 128.4, 128.7, 128.8, 131.3, 132.0, 134.9, 137.1, 140.0,140.7, 174.1; FTIR (Neat): 1716, 1487, 1270, 1243, 753 cm⁻¹; HRMS(pos-APCI) calcd for C₂₅H₂₃O₂: 355.16926. Found 355.16904.

(E)-methyl 1-(naphthalen-2-yl)-2-styrylcyclopropanecarboxylate (3d)

A solution of methyl 2-diazo-2-(naphthalen-2-yl)acetate (226 mg, 1 mmol,and 1 eq.) in toluene (10 mL) was added by syringe pump over 1 h to asolution of (E)-buta-1,3-dienylbenzene (390.2 mg, 3 mmol, 3 eq.) andRh₂(OAc)₄ (4 mg, 0.01 mmol, 0.1 eq.) in toluene (10 mL) at rt. Thereaction mixture was stirred at rt for an additional 2 h, and thenconcentrated in vacuo. Crude reaction mixture was purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate295 mg (90% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.59 (dd,J=6.41, 4.58 Hz, 1H) 2.12 (dd, J=9.00, 4.42 Hz, 1H) 2.75 (td, J=9.31,6.71 Hz, 1H) 3.58 (s, 3H) 5.20 (dd, J=15.87, 9.76 Hz, 1H) 6.60 (d,J=15.56 Hz, 1H) 7.01-7.14 (m, 5H) 7.42 (dt, J=6.41, 3.20 Hz, 3H)7.72-7.81 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 22.6, 32.1, 35.7, 52.4,125.7, 125.9, 126.9, 127.4, 127.5, 127.7, 128.3, 128.5, 129.9, 129.9,131.3, 132.5, 133.0, 133.5, 136.9, 174.0; FT-IR (neat): 1715, 1434,1270, 1244, 906, 728 cm⁻¹; HRMS (pos-APCI) calcd for C₂₃H₂₁O₂:329.15361. Found: 329.15347.

(E)-methyl 1-(3,4-dichlorophenyl)-2-styrylcyclopropanecarboxylate (3e)

A solution of methyl 2-diazo-2-(3,4-dichlorophenyl)acetate (490 mg, 2mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump over 1 hto a solution of (E)-buta-1,3-dienylbenzene (781 mg, 6 mmol, 3 eq.) andRh₂(OAc)₄ (8 mg, 0.01 mmol, 0.1 eq.) in toluene (10 mL) at rt. Thereaction mixture was stirred at rt for an additional 2 h, and thenconcentrated in vacuo. Crude reaction mixture was purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate659 mg (95% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.42 (dd,J=6.56, 4.73 Hz, 1H) 2.06 (dd, J=9.00, 4.73 Hz, 1H) 2.68 (td, J=9.23,6.86 Hz, 1H) 3.64 (s, 3H) 5.18 (dd, J=15.71, 9.61 Hz, 1H) 6.59 (d,J=15.87 Hz, 1H) 7.10-7.15 (m, 3H) 7.17 (d, J=7.02 Hz, 1H) 7.20-7.26 (m,2H) 7.36 (d, J=8.24 Hz, 1H) 7.40 (d, J=1.83 Hz, 1H); ¹³C NMR (75 MHz,CDCl₃) δ 22.5, 32.0, 34.7, 52.6, 125.9, 127.3, 127.5, 128.4, 129.9,131.2, 131.5, 132.0, 132.2, 133.3, 136.1, 136.7, 173.0; FT-IR (neat):1717, 1473, 1272, 1241, 956, 753, 727 cm⁻¹; HRMS (pos-APCI) calcd forC₁₉H₁₅O₂ ³⁵Cl₂: 345.04546 Found: 345.04542.

(E)-methyl 1-(2-chlorophenyl)-2-styrylcyclopropanecarboxylate (3f)

A solution of methyl 2-(2-chlorophenyl)-2-diazoacetate (421 mg, 2 mmol,and 1 eq.) in toluene (10 mL) was added by syringe pump over 1 h to asolution of (E)-buta-1,3-dienylbenzene (781 mg, 6 mmol, 3 eq.) andRh₂(OAc)₄ (8 mg, 0.01 mmol, 0.1 eq.) in toluene (10 mL) at rt. Thereaction mixture was stirred at rt for an additional 2 h, and thenconcentrated in vacuo. Crude reaction mixture was purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate605 mg (97% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.49 (br.s., 1H) 1.92 (br. s., 1H) 2.89 (br. s., 1H) 3.57 (s, 3H) 5.30 (br. s.,1H) 6.52 (d, J=15.56 Hz, 1H) 7.03-7.20 (m, 7H) 7.27-7.33 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 22.2, 32.2, 35.1, 52.34, 125.71, 126.28, 126.94,128.24, 128.65, 129.38, 136.95, 137.00, 172.95; FT-IR (neat): 1718,1434, 1268, 1241, 953, 748 cm⁻¹; HRMS (pos-APCI) calcd for C₁₉H₁₈O₂³⁵Cl₁: 313.09898 Found: 313.09897.

(E)-methyl 1-(3,4-dimethoxyphenyl)-2-styrylcyclopropanecarboxylate (3 g)

A solution of methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate (472 mg, 2mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump over 1 hto a solution of (E)-buta-1,3-dienylbenzene (781 mg, 6 mmol, 3 eq.) andRh₂(OAc)₄ (8 mg, 0.01 mmol, 0.1 eq.) in toluene (10 mL) at rt. Thereaction mixture was stirred at rt for an additional 2 h, and thenconcentrated in vacuo. Crude reaction mixture was purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate621 mg (92% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.40-1.46(m, 1H) 2.03 (dd, J=8.85, 4.27 Hz, 1H) 2.60-2.70 (m, 1H) 3.60 (s, 3H)3.73 (s, 3H) 3.81 (s, 3H) 5.25 (dd, J=15.87, 9.76 Hz, 1H) 6.56 (d,J=15.87 Hz, 1H) 6.75-6.88 (m, 3H) 7.07-7.20 (m, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 22.6, 31.6, 34.9, 52.0, 55.3, 55.3, 110.2, 114.5, 123.3, 125.4,126.7, 127.9, 128.1, 128.7, 130.7, 136.7, 147.8, 147.9, 173.8 FT-IR(neat): 1715, 1516, 1246, 1226, 756, 727 cm⁻¹; HRMS (pos-APCI) calcd forC₂₁H₂₃O₄: 339.15909. Found: 339.15894.

Synthesis of Formyl Cyclopropanecarboxylates (4) Methyl2-formyl-1-phenylcyclopropanecarboxylate (4a)

Ozone was bubbled through a solution of (E)-methyl1-phenyl-2-styrylcyclopropanecarboxylate (835 mg, 3 mmol, 1 eq.) in DCM(10 mL) at −78° C. until the blue color of ozone persists. The reactionmixture was warmed to rt and PPh₃ was added. The resultant mixture wasstirred at rt for 2 h, and then concentrated in vacuo. Purified by flashchromatography on silica gel using 9:1 hexane/EtOAc as eluant to isolate623 mg (86% yield) of oily liquid. ¹H NMR (400 MHz, CDCl₃) δ 2.03-2.08(m, 1H) 2.10 (dd, J=8.54, 4.88 Hz, 1H) 2.71 (dd, J=8.54, 6.41 Hz, 1H)3.62 (s, 3H) 7.25-7.34 (m, 5H) 8.53 (d, J=6.41 Hz, 1H); ¹³C NMR (75 MHz,CDCl₃) δ 19.1, 36.1, 37.2, 52.8, 128.0, 128.4, 130.8, 133.5, 171.8,198.1; FT-IR (neat): 1706, 1249, 1155, 699 cm⁻¹; HRMS (pos-APCI) calcdfor C₁₅H₁₉O₃: 247.13287 Found: 247.13284.

Methyl 1-(4-bromophenyl)-2-formylcyclopropanecarboxylate (4b)

Ozone was bubbled through a solution of (E)-methyl1-(4-bromophenyl)-2-styrylcyclopropanecarboxylate (535 mg, 1.5 mmol, 1eq.) in DCM (10 mL) at −78° C. until the blue color of ozone persists.The reaction mixture was warmed to rt and PPh₃ was added. The resultantmixture was stirred at rt for 2 h, and then concentrated in vacuo.Purified by flash chromatography on silica gel using 9:1 hexane/EtOAc aseluant to isolate 401 mg (93% yield) of oily liquid. ¹H NMR (400 MHz,CDCl₃) δ 2.01-2.08 (m, 1H) 2.12 (dd, J=8.70, 5.03 Hz, 1H) 2.77 (dt,J=8.54, 6.25 Hz, 1H) 3.65 (s, 3H) 7.18 (d, J=8.54 Hz, 2H) 7.42-7.52 (m,2H) 8.64 (d, J=6.10 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 19.0, 35.9,36.7, 52.8, 121.9, 128.1, 129.8, 131.4, 132.4, 133.3, 171.1, 197.5; FTIR(Neat): 1707, 1450, 1250, 1157, 713 cm⁻¹; HRMS (pos-API) calcd forC₂₁H₁₀O₄Br: 296.97679. Found 296.97673.

Methyl 1-([1,1′-biphenyl]-4-yl)-2-formylcyclopropanecarboxylate (4c)

Ozone was bubbled through a solution of (E)-methyl1-([1,1′-biphenyl]-4-yl)-2-styrylcyclopropanecarboxylate (531 mg, 1.5mmol, 1 eq.) in DCM (10 mL) at −78° C. until the blue color of ozonepersists. The reaction mixture was warmed to rt and PPh₃ was added. Theresultant mixture was stirred at rt for 2 h, and then concentrated invacuo. Purified by flash chromatography on silica gel using 9:1hexane/EtOAc as eluant to isolate 355 mg (83% yield) of oily liquid. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.03-2.19 (m, 2H) 2.70-2.82 (m, 1H) 3.61 (s,3H) 7.28-7.45 (m, 5H) 7.54 (dd, J=7.32, 6.10 Hz, 4H) δ 8.59 (d, J=6.41Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 198.06, 171.7, 140.7, 140.0, 133.3,132.4, 131.1, 129.8, 128.5, 128.2, 127.3, 127.0, 126.8, 52.7, 36.9,36.1, 19.1; FTIR (Neat): 1707, 1487, 1249, 1155, 763 cm⁻¹; HRMS(Pos-API) calcd for C₁₈H₁₅O₃: 279.10267. Found 279.10253.

Methyl 2-formyl-1-(naphthalen-2-yl)cyclopropanecarboxylates (4d)

Ozone was bubbled through a solution of (E)-methyl1-(naphthalen-2-yl)-2-styrylcyclopropanecarboxylate (492 mg, 1.5 mmol, 1eq.) in DCM (10 mL) at −78° C. until the blue color of ozone persists.The reaction mixture was warmed to rt and PPh₃ was added. The resultantmixture was stirred at rt for 2 h, and then concentrated in vacuo.Purified by flash chromatography on silica gel using 9:1 hexane/EtOAc aseluant to isolate 202 mg (53% yield) of oily liquid. ¹H NMR (400 MHz,CDCl₃) δ 2.21 (d, J=7.63 Hz, 2H) 2.81 (q, J=7.22 Hz, 1H) 3.64 (s, 3H)7.40 (dd, J=8.70, 1.07 Hz, 1H) 7.45-7.55 (m, 2H) 7.81 (d, J=8.24 Hz, 4H)8.56 (d, J=6.71 Hz, 1H) ¹³C NMR (75 MHz, CDCl₃) δ 19.2, 36.0, 36.6,53.0, 130.2, 130.3, 132.3, 132.4, 132.7, 133.8, 134.9, 139.3, 141.0,141.2, 170.94, 197.05; FT-IR (neat): 1706, 1435, 1252, 1153, 733 cm⁻¹;HRMS (pos-APCI) calcd for C₁₆H₁₃O₃: 253.08702 Found: 253.08691.

Methyl 1-(3,4-dichlorophenyl)-2-formylcyclopropanecarboxylate (4e)

Ozone was bubbled through a solution of (E)-methyl1-(3,4-dichlorophenyl)-2-styrylcyclopropanecarboxylate (520 mg, 1.5mmol, 1 eq.) in DCM (10 mL) at −78° C. until the blue color of ozonepersists. The reaction mixture was warmed to rt and PPh₃ was added. Theresultant mixture was stirred at rt for 2 h, and then concentrated invacuo. Purified by flash chromatography on silica gel using 9:1hexane/EtOAc as eluant to isolate 331 mg (80% yield) of oily liquid. ¹HNMR (400 MHz, CDCl₃) δ 2.03-2.08 (m, 1H) 2.13 (dd, J=8.70, 5.03 Hz, 1H)2.80 (dt, J=8.47, 6.14 Hz, 1H) 3.67 (s, 3H) 7.14 (dd, J=8.24, 1.83 Hz,1H) 7.39-7.45 (m, 2H) 8.74 (d, J=5.80 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ19.2, 36.0, 36.6, 53.0, 130.3, 130.3, 132.3, 132.4, 132.7, 133.8, 170.9,197.0; FT-IR (neat): 1707, 1474, 1247, 1159, 726 cm⁻¹; HRMS (pos-APCI)calcd for C₁₂H₉O₃Cl₂: 270.99342 Found: 270.99337.

Methyl 1-(2-chlorophenyl)-2-formylcyclopropanecarboxylate (4f)

Ozone was bubbled through a solution of (E)-methyl1-(2-chlorophenyl)-2-styrylcyclopropanecarboxylate (312 mg, 1 mmol, 1eq.) in DCM (10 mL) at −78° C. until the blue color of ozone persists.The reaction mixture was warmed to rt and PPh₃ was added. The resultantmixture was stirred at rt for 2 h, and then concentrated in vacuo.Purified by flash chromatography on silica gel using 9:1 hexane/EtOAc aseluant to isolate 166 mg (70% yield) of oily liquid. ¹H NMR (400 MHz,CDCl₃) δ 1.90-2.29 (m, 2H) 3.11 (br. s., 1H) 3.66 (s, 3H) 7.18-7.54 (m,4H) 8.95 (br. s., 1H); ¹³C NMR (75 MHz, CDCl₃) δ 20.4, 36.1, 53.1,127.0, 128.4, 129.5, 129.6, 130.1, 131.9, 133.6, 171.2, 196.2; FT-IR(neat): 1708, 1435, 1250, 1158, 727 cm⁻¹; HRMS (pos-APCI) calcd forC₁₂H₁₀O₃Cl: 237.03240 Found: 237.03194.

Synthesis of Methylamino Cyclopropanecarboxylates (5) Methyl2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate (5a)

In a 100 mL round bottom flask equipped with a magnetic stir bar, methyl2-formyl-1-phenylcyclopropanecarboxylate (612 mg, 3 mmol) was dissolvedin methanol (50 mL) and flushed with argon. This solution was treatedwith methylamine (2M in MeOH, 3 mL, 6 mmol) and Ti(O-iPr)₄ (2.4 mL, 6mmol) and stirred at room temperature for 16 hours. After the allottedtime had passed, NaBH₄ (170 mg, 4.5 mmol) was added and the reaction wasstirred for an additional 2 hours. The reaction was quenched with H₂O (1mL) and filtered through a short path of celite and rinsed with diethylether. The organic filtrate was diluted with diethyl ether and washedwith water, then brine, and dried over MgSO₄. The organic phase was thenfiltered and concentrated under reduced pressure and the resultingresidue was purified by column chromatography (SiO₂, Isolera, ethylacetate: triethylamine=9:1) to give a colorless oil in 63% yield (416mg). ¹H NMR (400 MHz, CDCl₃) δ 1.24 (dd, J=6.41, 4.58 Hz, 1H) 1.74 (dd,J=9.15, 4.27 Hz, 1H) 1.90-2.00 (m, 1H) 2.02-2.14 (m, 1H) 2.32 (s, 3H)2.45 (dd, J=12.36, 5.95 Hz, 1H) 3.62 (s, 3H) 7.15-7.49 (m, 5H); ¹³C NMR(75 MHz, CDCl₃) δ 20.0, 27.7, 33.0, 36.1, 52.1, 127.0, 127.8, 130.85,135.61, 174.35; FT-IR (neat): 2949, 2843, 1715, 1434, 1251, 700 cm⁻¹;HRMS (pos-APCI) calcd for C₁₃H₁₈O₂N, 220.13321 Found: 220.13306.

Methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate fumarate(5a salt)

Methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate (471 mg,2.1 mmol) was dissolved in isopropanol (20 mL) and then treated withfumaric acid (249 mg, 2.1 mmol) and stirred for 30 minutes at roomtemperature. The mixture was then concentrated under reduced pressureand the residue was re-dissolved in 2:1:1 isopropanol/hexanes/ethylacetate (10 mL) and refluxed for 2 hours. The solution was cooled toroom temperature and then to −20° C. using an acetone/ice bath. Theresulting solid was filtered and washed with cold acetone to giveoff-white solid. ¹H NMR (400 MHz, CD₃OD) δ 1.47-1.58 (m, 1H) 1.78 (dd,J=8.54, 4.88 Hz, 1H) 1.95 (dd, J=12.51, 10.98 Hz, 1H) 2.12-2.24 (m, 1H)2.59 (s, 3H) 3.23 (dd, J=12.81, 3.97 Hz, 1H) 3.58 (s, 3H) 6.67 (s, 2H)7.26-7.38 (m, 5H); ¹³C NMR (75 MHz, CD₃OD) δ 21.0, 23.5, 33.4, 33.4,34.8, 51.1, 53.3, 129.1, 129.7, 132.3, 135.8, 136.3, 171.5, 175.0; FT-IR(neat): 3000, 1713, 1560, 1261, 1171, 702 cm⁻¹; HRMS (pos-APCI) calcdfor C₁₃H₁₈O₂N, 220.13321. Found: 220.13298.

Methyl 1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate(5b)

In a 100 mL round bottom flask equipped with a magnetic stir bar, methyl1-(4-bromophenyl)-2-formylcyclopropanecarboxylate (283 mg, 1 mmol) wasdissolved in methanol (20 mL) and flushed with argon. This solution wastreated with methylamine (2M in MeOH, 0.5 mL, 2 mmol) and Ti(O-iPr)₄(0.4 mL, 2 mmol) and stirred at room temperature for 16 hours. After theallotted time had passed, NaBH₄ (56 mg, 1.5 mmol) was added and thereaction was stirred for an additional 2 hours. The reaction wasquenched with H₂O (1 mL) and filtered through a short path of celite andrinsed with diethyl ether. The organic filtrate was diluted with diethylether and washed with water, then brine, and dried over MgSO₄. Theorganic phase was then filtered and concentrated under reduced pressureand the resulting residue was purified by column chromatography (SiO₂,Isolera, ethyl acetate: triethylamine=9:1) to give colorless oil in 56%yield (166 mg). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (dd, J=6.56, 4.42 Hz, 1H)1.24 (br. s., 1H) 1.75 (dd, J=8.85, 4.27 Hz, 1H) 1.92-2.00 (m, 1H)2.01-2.12 (m, 1H) 2.32 (s, 3H) 2.42 (dd, J=12.20, 5.80 Hz, 1H) 3.60 (s,3H) 7.19 (d, J=8.24 Hz, 2H) 7.44 (d, J=8.24 Hz, 2H); ¹³C NMR (75 MHz,CDCl₃): δ 20.1, 27.7, 32.5, 36.2, 52.0, 52.2, 121.1, 131.0, 132.5,134.7, 173.8; FTIR (Neat): 1707, 1474, 1247, 1159, 726 cm⁻¹; HRMS(Pos-APCI) calcd for C₁₂H₉O₃Cl₂: 270.99342. Found 270.99337.

Methyl 1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylatefumarate (5b salt)

Methyl 1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate(298 mg, 1 mmol) was dissolved in isopropanol (20 mL) and then treatedwith fumaric acid (116 mg, 1 mmol) and stirred for 30 minutes at roomtemperature. The mixture was then concentrated under reduced pressureand the residue was re-dissolved in 2:1:1 isopropanol/hexanes/ethylacetate (10 mL) and refluxed for 2 hours. The solution was cooled toroom temperature and then to −20° C. using an acetone/ice bath. Theresulting solid was filtered and washed with cold acetone to giveoff-white solid. ¹H NMR (400 MHz, CD₃OD) δ 1.47-1.55 (m, 1H) 1.82 (dd,J=8.39, 4.73 Hz, 1H) 1.99 (dd, J=12.51, 10.98 Hz, 1H) 2.13-2.26 (m, 1H)2.63 (s, 3H) 3.27 (dd, J=12.66, 3.81 Hz, 1H) 3.63 (s, 3H) 6.68 (s, 2H)7.25 (d, J=8.24 Hz, 2H) 7.53 (d, J=8.24 Hz, 2H); ¹³C NMR (75 MHz, CD₃OD)δ 21.1, 23.6, 33.6, 34.3, 51.1, 53.4, 123.1, 132.8, 134.3, 135.1, 136.3,171.5, 174.5; FT-IR (neat): 3027, 2954, 2768, 1720, 1262 cm⁻¹; HRMS(pos-APCI) calcd for C₁₃H₁₇O₂N, 298.04372 Found: 298.04364.

Methyl1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylatehydrochloride (5c salt)

In a 100 mL round bottom flask equipped with a magnetic stir bar, methyl1-([1,1′-biphenyl]-4-yl)-2-formylcyclopropanecarboxylate (280 mg, 1mmol) was dissolved in methanol (20 mL) and flushed with argon. Thissolution was treated with methylamine (2M in MeOH, 0.5 mL, 2 mmol) andTi(O-iPr)₄ (0.4 mL, 2 mmol) and stirred at room temperature for 16hours. After the allotted time had passed, NaBH₄ (56 mg, 1.5 mmol) wasadded and the reaction was stirred for an additional 2 hours. Thereaction was quenched with H₂O (1 mL) and filtered through a short pathof celite and rinsed with diethyl ether. The organic filtrate wasdiluted with diethyl ether and washed with water, then brine, and driedover MgSO₄. The organic phase was then filtered and concentrated underreduced pressure and the resulting residue was purified by columnchromatography (SiO₂, Isolera, ethyl acetate: triethylamine=9:1) to givecolorless oil in 78% yield (230 mg). The product was dissolved indiethyl ether (15 mL), then treated with hydrochloric acid in diethylether (2M in diethyl ether, 1 mL), and the resulting white solid wasfiltered and washed with diethyl ether to obtain white solid. ¹H NMR(400 MHz, CDCl₃) δ 1.27 (dd, J=6.41, 4.58 Hz, 1H) 1.65 (br. s., 1H) 1.76(dd, J=8.70, 4.42 Hz, 1H) 1.95-2.04 (m, 1H) 2.05-2.13 (m, 1H) 2.31 (s,3H) 2.48 (dd, J=12.20, 5.80 Hz, 1H) 3.60 (s, 3H) 7.29-7.37 (m, 3H)7.38-7.45 (m, 2H) 7.56 (dd, J=16.78, 7.63 Hz, 4H); ¹³C NMR (75 MHz,CDCl₃) δ 20.1, 27.7, 32.7, 36.1, 52.0, 52.2, 126.6, 126.8, 127.0, 128.5,131.2, 134.5, 139.8, 140.4, 174.3; FT-IR (neat): 1716, 1487, 1434, 1250,1010, 763 cm⁻¹; HRMS (pos-APCI) calcd for C₁₉H₂₂O₂N₁: 296.16451 Found:296.16429

Methyl2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylatehydrochloride (5d salt)

In a 100 mL round bottom flask equipped with a magnetic stir bar, methyl2-formyl-1-(naphthalen-2-yl)cyclopropanecarboxylate (254 mg, 1 mmol) wasdissolved in methanol (20 mL) and flushed with argon. This solution wastreated with methylamine (2M in MeOH, 0.5 mL, 2 mmol) and Ti(O-iPr)₄(0.4 mL, 2 mmol) and stirred at room temperature for 16 hours. After theallotted time had passed, NaBH₄ (56 mg, 1.5 mmol) was added and thereaction was stirred for an additional 2 hours. The reaction wasquenched with H₂O (1 mL) and filtered through a short path of celite andrinsed with diethyl ether. The organic filtrate was diluted with diethylether and washed with water, then brine, and dried over MgSO₄. Theorganic phase was then filtered and concentrated under reduced pressureand the resulting residue was purified by column chromatography (SiO₂,Isolera, ethyl acetate: triethylamine=9:1) to give colorless oil in 60%yield (161 mg). The product was dissolved in diethyl ether (15 mL), thentreated with hydrochloric acid in diethyl ether (2M in diethyl ether, 1mL), and the resulting white solid was filtered and washed with diethylether to obtain white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.28 (br. s., 1H)1.37 (dd, J=6.56, 4.42 Hz, 1H) 1.81 (dd, J=8.85, 4.27 Hz, 1H) 1.90-2.05(m, 1H) 2.08-2.20 (m, 1H) 2.27 (s, 3H) 2.46 (dd, J=12.51, 6.10 Hz, 1H)3.60 (s, 3H) 7.41-7.49 (m, 3H) 7.72 (s, 1H) 7.79 (d, J=8.54 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 20.2, 28.0, 33.2, 36.2, 52.0, 52.2, 125.8, 125.9,127.3, 127.4, 127.6, 129.1, 129.3, 132.4, 133.0, 133.3, 174.4; FT-IR(neat): 1715, 1433, 1255, 1165, 749 cm⁻¹; HRMS (pos-APCI) calcd forC₁₇H₂₀O₂N, 270.14886 Found: 270.14880.

Methyl1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate(5e)

In a 100 mL round bottom flask equipped with a magnetic stir bar, methyl1-(3,4-dichlorophenyl)-2-formylcyclopropanecarboxylate (819 mg, 3 mmol)was dissolved in methanol (50 mL) and flushed with argon. This solutionwas treated with methylamine (2M in MeOH, 3 mL, 6 mmol) and Ti(O-iPr)₄(2.4 mL, 6 mmol) and stirred at room temperature for 16 hours. After theallotted time had passed, NaBH₄ (170 mg, 4.5 mmol) was added and thereaction was stirred for an additional 2 hours. The reaction wasquenched with H₂O (1 mL) and filtered through a short path of celite andrinsed with diethyl ether. The organic filtrate was diluted with diethylether and washed with water, then brine, and dried over MgSO₄. Theorganic phase was then filtered and concentrated under reduced pressureand the resulting residue was purified by column chromatography (SiO₂,Isolera, ethyl acetate: triethylamine=9:1) to give colorless oil in 57%yield (491 mg). ¹H NMR (400 MHz, CDCl₃) δ 1.18 (dd, J=6.41, 4.58 Hz, 1H)1.77 (dd, J=8.70, 4.42 Hz, 1H) 1.94-2.13 (m, 2H) 2.35 (s, 3H) 2.43 (dd,J=11.75, 5.34 Hz, 1H) 3.63 (s, 3H) 7.16 (dd, J=8.24, 1.83 Hz, 1H) 7.26(s, 1H) 7.38-7.43 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 20.3, 28.0, 32.4,36.3, 52.0, 52.4, 129.9, 130.5, 131.3, 131.9, 132.8, 136.1, 173.5; FT-IR(neat): 2950, 2843, 1718, 1474, 1247 cm⁻¹; HRMS (pos-APCI) calcd forC₁₃H₁₆O₂NCl₂: 288.05526 Found: 288.05516.

Methyl1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylatefumarate (5e salt)

Methyl1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate(288 mg, 1 mmol) was dissolved in isopropanol (20 mL) and then treatedwith fumaric acid (116 mg, 1 mmol) and stirred for 30 minutes at roomtemperature. The mixture was then concentrated under reduced pressureand the residue was re-dissolved in 2:1:1 isopropanol/hexanes/ethylacetate (10 mL) and refluxed for 2 hours. The solution was cooled toroom temperature and then to −20° C. using an acetone/ice bath. Theresulting solid was filtered and washed with cold acetone to giveoff-white solid. ¹H NMR (400 MHz, CD₃OD) δ 1.47-1.56 (m, 1H) 1.81 (dd,J=8.39, 5.03 Hz, 1H) 1.94-2.05 (m, 1H) 2.11-2.24 (m, 1H) 2.62 (s, 3H)3.62 (s, 3H) 6.66 (s, 2H) 7.25 (dd, J=8.24, 1.83 Hz, 1H) 7.48-7.54 (m,2H); ¹³C NMR (75 MHz, CD₃OD) δ 21.2, 23.8, 33.5, 33.5, 34.0, 50.9, 53.5,131.7, 132.3, 133.2, 133.5, 134.4, 136.3, 136.7, 171.5, 174.1; FT-IR(neat): 3022, 2771, 1719, 1270 cm⁻¹; HRMS (pos-APCI) calcd forC₁₃H₁₆O₂NCl₂: 288.05526 Found: 288.05525.

Methyl 1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate(5f)

In a 50 mL round bottom flask equipped with a magnetic stir bar, methyl1-(2-chlorophenyl)-2-formylcyclopropanecarboxylate (238 mg, 1 mmol) wasdissolved in methanol (20 mL) and flushed with argon. This solution wastreated with methylamine (2M in MeOH, 0.5 mL, 2 mmol) and Ti(O-iPr)₄(0.4 mL, 2 mmol) and stirred at room temperature for 16 hours. After theallotted time had passed, NaBH₄ (56 mg, 1.5 mmol) was added and thereaction was stirred for an additional 2 hours. The reaction wasquenched with H₂O (1 mL) and filtered through a short path of celite andrinsed with diethyl ether. The organic filtrate was diluted with diethylether and washed with water, then brine, and dried over MgSO₄. Theorganic phase was then filtered and concentrated under reduced pressureand the resulting residue was purified by column chromatography (SiO₂,Isolera, ethyl acetate: triethylamine=9:1) to give colorless oil in 60%yield (152 mg). ¹H NMR (400 MHz, CDCl₃) δ 1.28 (br. s., 1H) 1.41 (br.s., 1H) 1.59-1.86 (m, 2H) 2.34 (s, 3H) 2.74 (dd, J=12.36, 5.03 Hz, 1H)3.59 (s, 3H) 7.20-7.31 (m, 2H) 7.35-7.40 (m, 1H); ¹³C NMR (75 MHz,CDCl₃) δ 20.6, 27.0, 32.2, 35.9, 50.8, 52.1, 126.4, 128.4, 129.1, 131.5,134.4, 136.4, 173.2; FT-IR (neat): 2949, 1719, 1434, 1266, 1249, 728cm⁻¹; HRMS (pos-APCI) calcd for C₁₃H₁₆ClO2N, 254.09423 Found: 254.09419.

Methyl 1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylatefumarate (5f salt)

Methyl 1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate(288 mg, 1 mmol) was dissolved in isopropanol (20 mL) and then treatedwith fumaric acid (116 mg, 1 mmol) and stirred for 30 minutes at roomtemperature. The mixture was then concentrated under reduced pressureand the residue was re-dissolved in 2:1:1 isopropanol/hexanes/ethylacetate (10 mL) and refluxed for 2 hours. The solution was cooled toroom temperature and then to −20° C. using an acetone/ice bath. Theresulting solid was filtered and washed with cold acetone to giveoff-white solid. ¹H NMR (400 MHz, CD₃OD) δ 1.56-1.77 (m, 2H) 1.90 (br.s., 1H) 2.43 (br. s., 1H) 2.61 (s, 3H) 3.43 (d, J=10.37 Hz, 1H) 3.60 (s,3H) 6.66 (s, 2H) 7.30-7.39 (m, 3H) 7.41-7.47 (m, 1H); ¹³C NMR (75 MHz,CD₃OD) δ 33.44, 33.47, 53.45, 128.74, 130.82, 130.98, 133.85, 134.64,136.35, 171.56, 174.09

Methyl1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylatehydrochloride (5 g salt)

In a 50 mL round bottom flask equipped with a magnetic stir bar, crudemixture of methyl1-(3,4-dimethoxyphenyl)-2-formylcyclopropanecarboxylate (264 mg, 1 mmol)was dissolved in methanol (20 mL) and flushed with argon. This solutionwas treated with methylamine (2M in MeOH, 0.5 mL, 2 mmol) and Ti(O-iPr)₄(0.4 mL, 2 mmol) and stirred at room temperature for 16 hours. After theallotted time had passed, NaBH₄ (56 mg, 1.5 mmol) was added and thereaction was stirred for an additional 2 hours. The reaction wasquenched with H₂O (1 mL) and filtered through a short path of celite andrinsed with diethyl ether. The organic filtrate was diluted with diethylether and washed with water, then brine, and dried over MgSO₄. Theorganic phase was then filtered and concentrated under reduced pressureand the resulting residue was purified by column chromatography (SiO₂,Isolera, ethyl acetate: triethylamine=9:1) to give colorless oil in 56%yield (156 mg) over two steps. The product was dissolved in diethylether (15 mL), then treated with hydrochloric acid in diethyl ether (2Min diethyl ether, 1 mL), and the resulting white solid was filtered andwashed with diethyl ether to obtain white solid. ¹H NMR (400 MHz, CDCl₃)δ 1.10 (t, J=5.03 Hz, 1H) 1.19 (br. s., 1H) 1.61 (dd, J=7.93, 3.97 Hz,1H) 1.94 (d, J=7.93 Hz, 2H) 2.23 (s, 3H) 2.30-2.40 (m, 1H) 3.51 (s, 3H)3.77 (d, J=1.83 Hz, 6H) 6.75 (d, J=16.48 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 20.1, 27.7, 32.6, 36.1, 51.9, 51.9, 55.3, 55.5, 110.2, 113.9,122.8, 127.9, 147.84, 148.0, 174.4; FT-IR (neat): 2950, 2837, 1715,1516, 1249, 1226, 726 cm⁻¹; HRMS (pos-APCI) calcd for C₁₅H₂₂O₄N,280.15433 Found: 280.15430.

(1R,2S)-methyl 1-phenyl-2-((E)-styryl)cyclopropanecarboxylate

A solution of methyl 2-diazo-2-phenylacetate (250 mg, 1 mmol, and 1 eq.)in hexane (5 mL) was added by syringe pump over 1 hr to a solution of(E)-buta-1,3-dienylbenzene (390.2 mg, 3 mmol, 3 eq.) and Rh₂ (S-DOSP)₄(18 mg, 0.01 mmol, 0.1 eq.) in hexane (50 mL) at −45° C. The reactionmixture was stirred at −45° C. for an additional 2 h, and thenconcentrated in vacuo. Purified by flash chromatography on silica gelusing 9:1 hexane/EtOAc as eluant to isolate colored oily liquid, 232 mg(83%). >94% de and 96% ee. ¹H NMR (500 MHz, CDCl₃): δ7.25 (m, 5H), 7.12(m, 2H), 7.05 (m, 3H), 6.52 (d, J=15.5 Hz, 1H), 5.18 (dd, J=15.5 Hz,10.0 Hz, 1H), 3.52 (s, 3H), 2.66 (m, 1H) 2.02 (m, 1H), 1.42 (m, 1H). ¹³CNMR (300 MHz, CDCl₃): 6173.7 (C), 136.8 (C), 135.6 (C), 131.4 (CH),131.0 (CH), 128.5 (CH), 128.1 (CH), 127.8 (CH), 127.0 (CH), 126.8 (CH),125.6 (CH), 52.12 (CH₃), 35.47 (C), 31.65 (CH), 22.26 (CH₂). IR (CHCl₃):1717, 1271, 1244, 1193, 1159, 960, 752, 694 cm⁻¹. HRMS (EI) m/z calcdfor [C₁₉H₁₈O₂Na₁]⁺ 301.1199. Found: 301.1194. [α]²⁰ _(D)=−181° (10mg/mL, MeOH). HPLC analysis: 96% ee (Chiralcel SS-Whelk, 1% i-PrOH inhexane, 0.6 ml/min, λ=254 nm, t_(R)=24.3 min, minor; t_(R)=33.5 min,major).

(1S,2R)-methyl 1-phenyl-2-((E)-styryl)cyclopropanecarboxylate

The enantiomer was made using Rh₂(R-DOSP)₄ as catalyst in the samereaction conditions as described above, to obtain the 256 mg (92%). >94%de and 92% ee. [α]²⁰ _(D)=181° (10 mg/mL, MeOH). HPLC analysis: 96% ee(Chiralcel SS-Whelk, 1% i-PrOH in hexane, 0.6 ml/min, λ=254 nm,t_(R)=24.3 min, major; t_(R)=33.5 min, minor).

(1R,2R)-methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate

Ozone was bubbled through the solution of (E)-methyl1-(phenyl)-2-styrylcyclopropanecarboxylate (556 mg, 2 mmol, 1 eq.) inDCM at −78° C. until blue color of ozone persists. The reaction mixturewas stirred at −78° C. for an additional 2 h, and then PPh₃ was added.The crude mixture was concentrated in vacuo and dissolved in MeOH.Ti(O^(i)Pr)₄ and methylamine were added at RT and stirred for 2 hours.NaBH₄ was added in portions at RT. Bubbles were observed. The reactionmixture is quenched with H₂O, filtered through celite and extracted intoEtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuoto get crude mixture. The product was purified by flash chromatographyon silica gel using 9:1 EtOAc/Et₃N as eluant to isolate colorless oilyliquid, 271 mg (62% over 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.24 (dd,J=6.41, 4.58 Hz, 1H) 1.74 (dd, J=9.15, 4.27 Hz, 1H) 1.90-2.00 (m, 1H)2.02-2.14 (m, 1H) 2.32 (s, 3H) 2.45 (dd, J=12.36, 5.95 Hz, 1H) 3.62 (s,3H) 7.15-7.49 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 20.0, 27.7, 33.0, 36.1,52.1, 127.0, 127.8, 130.85, 135.61, 174.35; FT-IR (neat): 2949, 2843,1715, 1434, 1251, 700 cm⁻¹; HRMS (pos-APCI) calcd for C₁₃H₁₈O₂N,220.13321 Found: 220.13306.

(1S,2S)-methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate

The enantiomer was made using the same reaction conditions as describedabove, to obtain product in 59% yield (258 mg) over 2 steps.

Modifying the procedures above with appropriate starting materialsprovides desired products in disastereomeric excess. For example,reductive amination described herein to make the N-methyl derivativesmay be extended to a series of amines to generate a series offunctionalized amines below. Other examples are illustrated in FIG. 5.

Transporter Binding Studies

Affinities of analogs at dopamine transport (DAT) sites are determinedby displacement of [¹²⁵I]RTI-55 binding in membranes from rat striatum.See Boja et al., Eur. J. Pharmacol., 1991, 194, 133, hereby incorporatedby reference. Frozen brains from Sprague-Dawley rats are obtainedcommercially and striata are dissected on ice. Tissue is homogenized in10 vol of RTI-55 assay buffer (0.32 M sucrose, 10 mM sodium phosphatebuffer, pH 7.4) with a Polytron, and centrifuged three times at 48,000 gfor 10 min, with fresh buffer resuspension for each centrifugation.Assay tubes contain 0.5 mg (original wet weight) of membranes, 0.01 nM[¹²⁵I]RTI-55, and various concentrations of unlabeled drugs dissolved inRTI-55 assay buffer in a final volume of 2 ml. Tubes are incubated for50 min at 25° C., and the reaction is terminated by rapid filtrationwith 3-5 ml of cold Tris buffer through Whatman GF/B glass fiber filterspre-soaked in Tris buffer containing 0.1% BSA for at least 1 h.Non-specific binding is determined in the presence of 1 μMWF-23.

Affinities of analogs at 5-HT transport (SERT) sites are determined bydisplacement of [³H]citalopram binding in membranes from rat frontalcortex. See D'Amato et al., J. Pharmacol. Exp. Ther., 1987, 242, 364hereby incorporated by reference. Tissue is obtained from frozen ratbrains as described above, homogenized in vol of citalopram assay buffer(50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4) with a Polytron, andcentrifuged two times at 48,000 g for 10 min, with fresh bufferresuspension for each centrifugation. Assay tubes contain 50 mg(original wet weight) of membranes, 0.4 nM [³H]citalopram, and variousconcentrations of unlabeled drugs dissolved in citalopram assay bufferin a final volume of 2 ml. Tubes are incubated for 60 min at 25° C., andthe reaction is terminated by rapid filtration with 3×4 mL of cold Trisbuffer through Whatman GF/B glass fiber filters pre-soaked in Trisbuffer containing 0.1% BSA for at least 1 h. Non-specific binding isdetermined in the presence of 10 M fluoxetine.

Binding of analogs at norepinephrine transporters (NET) was determinedby displacement of [³H]nisoxetine binding. See Tejani-Butt, J.Pharmacol. Exp. Ther., 1991, 260, 427, hereby incorporated by reference.Whole rat brains (minus cerebellum) are homogenized in 30 vol of 120 mMNaCl, 5 mM KCl, 50 mM Tris-HCl, pH 7.4, and centrifuged at 48,000 g for10 min. The membranes are resuspended in nisoxetine assay buffer (300 mMNaCl, 5 mM KCl, 50 mM Tris-HCl, pH 7.4) and centrifuged again beforefinal resuspension in volumes of buffer. Assay tubes contain 7501 ofbrain membranes, [³H]nisoxetine (0.7 nM) together with unlabeled drugsdissolved in nisoxetine assay buffer to a final volume of 1 ml. Tubesare incubated for 40 min at 25° C., and the reaction is terminated byrapid filtration with 3×4 mL of cold Tris buffer through Whatman GF/Bglass fiber filters which have been pre-soaked in Tris buffer containing0.1% BSA for at least 1 h. Non-specific binding is determined in thepresence of 1 μM desipramine. In [³H]citalopram and [³H]nisoxetinebinding assays, radioactivity is determined by liquid scintillationspectrophotometry (efficiency: 50%) after eluting filters overnight in 5mL of Ecolite scintillation fluid (ICN). IC₅₀ values are calculated fromdisplacement curves using 7-10 concentrations of unlabeled analogs.Because binding of tropanes at dopamine transporter sites is generallyregarded as multiphasic, potencies in inhibiting [¹²⁵I]RTI-55 bindingare reported as IC₅₀ values. For [³H]paroxetine and [³H]nisoxetinebinding assays, Ki values are calculated using the Cheng-Prusoffequation. See Cheng & Prusoff, Biochem. Pharmacol., 1973, 22, 3099hereby incorporated by reference. In vitro data of cyclopropane aminesis provided in Table 1.

TABLE 1 Analog Ar Isomer Log-P NET SERT DAT HD-283 Milnacipran (S,R)1.91 23.8 ± 1.7  35.1 ± 4.4 1970 ± 230 HD-284 C₆H₅ ± 1.65 152 ± 65   157± 4.8 1780 ± 87  HD-285 4-BrC₆H₄ ± 2.51 3.7 ± 1.4 210 ± 10 1460 ± 470HD-286 4-PhC₆H₄ ± 3.54 315 ± 100 4.85 ± 1.0 189 ± 79 HD-287 2-naphthyl ±2.82 3.49 ± 0.64  6.58 ± 0.71 177 ± 44 HD-288 3,4-diClC₆H₃ ± 2.95 0.80 ±0.02  5.6 ± 0.39 107 ± 22 HD-289 3,4-di(OMe)C₆H₃ ± 1.31 8.62 ± 0.71 106± 21 1364 ± 198 HD-290 2-ClC₆H₄ ± 2.36 289 ± 24  329 ± 54 1840 ± 350HD-324 4-BrC₆H₄ (S,S) 2.51 44.9 ± 1.0  946 ± 71 >10,000 HD-325 4-BrC₆H₄(R,R) 2.51 2.49 ± 0.07 47.0 ± 2.9 333 ± 79 HD-326 3,4-diClC₆H₃ (S,S)2.95 8.11 ± 0.80 40.5 ± 4.3 299 ± 97 HD-327 3,4-diClC₆H₃ (R,R) 2.95 0.31± 0.01  2.42 ± 0.31 23.8 ± 3.6 HD-328 3,4-diBrC₆H₃ (S,S) 3.17 4.57 ±0.66 18.4 ± 2.5 87.9 ± 9.5 HD-329 3,4-diBrC₆H₃ (R,R) 3.17 0.62 ± 0.12 1.71 ± 0.05 35.2 ± 4.6 HD-330 2-naphthyl (S,S) 2.82 16.4 ± 0.52 27.0 ±3.4 313 ± 55 HD-331 2-naphthyl (R,R) 2.82 10.4 ± 0.89 15.0 ± 2.8 320 ±51 HD-332 4-PhC₆H₄ (S,S) 3.54 >10,000 79.8 ± 21  917 ± 62 HD-3334-PhC₆H₄ (R,R) 3.54 86.6 ± 19    2.69 ± 0.62 86.7 ± 37 

Analgesia Testing Methods: Spinal Nerve Ligation

A 3 cm incision was made in the back using the iliac crests as amidpoint. An incision was then made in the underlying muscle, which wasthen separated by both sharp and blunt dissection to expose the lefttransverse process of the fifth lumbar vertebra. The transverse processwas removed using bone microrongeurs, and the fifth lumbar nerve wasexteriorized from underneath the spinal column using a small metal hookand ligated using 4.0 silk suture with sufficient pressure to cause thenerve to bulge on each side of the ligature. The sixth lumbar nerve wasexteriorized from underneath the iliac bone at the sciatic notch andligated in a similar manner. All muscle layers were sutured using 4.0chromic gut, the skin was sutured using 4.0 nylon suture.

Intrathecal Catheter Implantation

The animal is placed in a stereotaxic frame to immobilize the head underpentobarbital anesthesia. The animal's body is lifted and supported torender the spinal column straight and level and the animal's head isplaced downward such the top of the skull forms a 90° angle with thespinal column. A small incision is placed at the back of the neck andthe underlying musles are blunt dissected to reveal theatlanto-occipital membrane. A small incision is placed in theatlanto-occipital membrane through which a 32 ga polyethylene catheteris inserted that is 8 cm in length. The catheter is anchored to the neckmuscles with 4.0 silk suture and the exterior wounds are closed with 4.0nylon suture.

Drug Administration

All compounds were dissolved in 0.9% (wt/vol) saline, pH 7.4 andadministered through the intrathecal catheter in a volume of 5 μl,followed by 15 μl of 0.9% saline to flush the catheter.

Determination of Mechanical Allodynia (Paw Withdrawal Threshold)

Paw withdrawal threshold was determined before and at selected timepoints following intrathecal drug administration using calibrated vonFrey filaments. The animals are placed in elevated Plexiglas chamberswith wire mesh floors and acclimated for a minimum of 30 minutes.Beginning with a filament calibrated to bend with a force of 2 g ofpressure, the filament is applied to the plantar surface of the lefthindpaw with sufficient force to bend slightly and left in place for 8seconds or until the animal withdraws it's paw from the filament. In theabsence of a paw withdrawal, the next highest calibrated filament isapplied in a similar manner. In the presence of a paw withdrawal, thenext lowest calibrated filament is applied. This up-down methodcontinues until 4 responses are recorded after an initial positiveresponse. The paw withdrawal threshold is calculated using Dixonnon-parametric statistics.

Anti-Allodynic Effects of Novel SNRI Analogs

The potency and efficacy of novel SNRI analogs in reversing mechanicalhypersensitivity were determined in the L5/L6 spinal nerve ligation(SNL) model of neuropathic pain in rats. Compounds were administeredintrathecal (i.t.) and the effect on paw withdrawal threshold wasassessed at various time points following treatment. The effects ofHD-288 (NET selective), HD-283 (milnacipran, non-selective), and HD-286(SERT selective) were determined and compared to those of clonidine, adrug approved for treatment of neuropathic pain in humans by spinaladministration.

HD-288 was potent following i.t. administration, producing significantanti-allodynic effects with an A50 of 0.6±0.3 μg and increasing the PWTfrom 2.9±0.4 g to 24.9±2.5 g at 3 μg. Clonidine (10 μg, i.t.) and HD-283(milnacipran, 30 μg, i.t.) reversed mechanical allodynia in SNL ratssimilar to literature values. HD-286 produced an increase in PWT in SNLrats over a similar dose range as HD-288 with significantly lowerefficacy, consistent with reports of the limited efficacy of SERTinhibitors against neuropathic pain (FIG. 3). The maximum effect ofHD-288 was found to be significantly greater than clonidine. Therefore,HD-288 appears to be efficacious in reversing a symptom of neuropathicpain (mechanical allodynia) in nerve-injured rats and is quite potentcompared to medications approved for clinical treatment of chronic pain(clonidine, milnacipran).

Effects of Novel SNRI Analogs on Sedation and/or Motor Coordination inthe Rotarod Assay

Rotarod performance was assessed to determine the relative potency ofnovel SNRI analogs as well as clonidine for producing sedation and/ormotor impairment, two important dose-limiting side effects of thesecompounds. Clonidine (10 μg, i.t.) decreased the time rats were able tostay on the rotarod by 35±10% of baseline values [F(1, 25)=12.3,p=0.002](FIG. 4). Administration of the maximum dose of HD-288 (3 μg,i.t.) had no significant effect on rotarod performance [F(1, 19)=1.02,p=0.3]. Sedation is a major dose-limiting side effect of clonidine andHD-288 appears to produce greater anti-allodynic effects and lesssedation than clonidine in the rat.

1. A compound comprising formula I:

or salts thereof wherein, A ring is a carbocyclyl, aryl, orheterocyclyl; n is 0, 1, 2, 3, 4, or 5; X and Y are the same ordifferent O, S, NR⁴; R¹ is hydrogen, alkyl, halogen, nitro, cyano,hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,alkylamino, (alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl,carbocyclyl, aryl, or heterocyclyl, wherein R¹ is optionally substitutedwith one or more, the same or different, R⁵; R² is hydrogen, alkyl,halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy,carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl,alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, whereinR² is optionally substituted with one or more, the same or different,R⁵; R³ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino,mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino,(alkyl)₂amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,aryl, or heterocyclyl, wherein R³ is optionally substituted with one ormore, the same or different, R⁵; R⁴ is hydrogen, alkyl, hydroxy, amino,formyl, carbocyclyl, aryl, or heterocyclyl, wherein R⁴ is optionallysubstituted with one or more, the same or different, R⁵; R⁵ is alkyl,halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy,carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl,alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, whereinR⁵ is optionally substituted with one or more, the same or different,R⁶; and R⁶ is halogen, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl,carbocyclyl, aryl, or heterocyclyl.
 2. A compound of formula I, whereinformula I is formula IA, IB, IC, or ID wherein: formula IA is

formula IB is

formula IC is

and formula ID is


3. A compound of claim 1, wherein the A ring is aryl.
 4. A compound ofclaim 1, wherein X is oxygen.
 5. A compound of claim 1, wherein Y isNR⁴.
 5. A compound of claim 1, wherein R³ is hydrogen or C₁₋₄alkyl.
 6. Acompound of claim 1, wherein R² is hydrogen or C₁₋₄alkyl.
 7. A compoundof claim 1, wherein R¹ is a hydrogen, halogen, or alkoxy.
 8. A compoundof claim 1 selected from: (1S,2S)-methyl2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate,(1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic acid,(1S,2S)-methyl1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1S,2S)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1S,2S)-methyl2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,(1S,2S)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylicacid, (1S,2S)-methyl1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,and(1S,2S)-1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, or salts thereof.
 9. A compound of claim 1 selected from:(1S,2S)-methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate,(1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic acid,(1R,2R)-methyl1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,(1R,2R)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, (1R,2R)-methyl2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,(1R,2R)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylicacid, (1R,2R)-methyl1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,and(1R,2R)-1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylicacid, or salts thereof.
 10. A composition comprising a compound of claim1 in greater than 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.5%diastereomeric excess.
 11. An isolated composition of a compound ofclaim 1 in substantially pure form.
 12. A pharmaceutical compositioncomprising a compound of claim 1 or pharmaceutically acceptable salt orprodrug thereof.
 13. A pharmaceutical composition of claim 12 furthercomprising a second therapeutic agent.
 14. A method of treating orpreventing a medical disorder comprising administering a pharmaceuticalcomposition of claim 12 to a subject diagnosed with, exhibiting symptomsof, or at risk of a medical disorder.
 15. The method of claim 14,wherein the medical disorder is mental disorder.
 16. A method ofmanaging neuropathic pain comprising administering a pharmaceuticalcomposition of claim 12 to a subject in need thereof.
 17. A method oftreating fibromyalgia comprising administering a pharmaceuticalcomposition of claim 12 to a subject in need thereof.
 18. A process ofproducing a compound of formula I comprising mixing a metal catalyst, acompound of formula II, formula II

and a compound of formula III, formula III

under conditions such that a compound of formula I is formed.
 19. Theprocess of claim 18, wherein the metal catalyst is a chiral catalyst.20. The process of claim 18, wherein the metal catalyst isRh₂(S-biTISP)₂, Rh₂(S-DOSP)₄, or Rh₂(S-PTAD)₄.